Thienopyrimidine inhibitors of atypical protein kinase C

ABSTRACT

The present application provides a compound of formula (I) 
                         
or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/285,007, now U.S. Pat. No. 9,604,994, filed May 22, 2014, which is aU.S. National Phase application under 35 U.S.C. § 371 of InternationalPatent Application No. PCT/US2012/065831, filed Nov. 19, 2012, whichclaims the benefit of U.S. Provisional Application No. 61/563,310, filedNov. 23, 2011, the content of each of which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

PKCι and PKCζ (accession numbers NM_002740 and NM_002744 respectively)together define the atypical sub-class of the protein kinase C (PKC)family (aPKCs). The aPKCs are structurally and functionally distinctfrom the other PKC sub-classes, classic/conventional and novel, as theircatalytic activity is not dependent on diacylglycerol and calcium (Ono,Y., Fujii, T., Ogita, K., Kikkawa, U., Igarashi, K., and Nishizuka, Y.(1989). Protein kinase C zeta subspecies from rat brain: its structure,expression, and properties. Proc Natl Acad Sci USA 86, 3099-3103).Structurally, PKCι and PKCζ contain a C-terminal serine/threonine kinasedomain (AGC class) and an N-terminal regulatory region containing a PhoxBem 1 (PB1) domain involved in mediating protein:protein interactionscritical for aPKC function. At the amino acid level the aPKCs share 72%overall homology, however, the kinase domains share 84% identity anddiffer in the active site by just a single amino acid. This strikinghomology suggests an ATP-competitive ligand would not be expected toexhibit significant aPKC isoform selectivity.

The aPKCs have been implicated in a diverse number of signallingpathways, demonstrating both redundant and distinct signallingfunctions. Both isoforms have emerged as central players in themechanisms that regulate the establishment and maintenance of cellularpolarity in multiple cell types (reviewed in Suzuki, A., and Ohno, S.(2006). The PAR-aPKC system: lessons in polarity. J Cell Sci 119,979-987). Genetic dissection of their functions using knockout mice havealso revealed preferential roles for PKC in the regulation of NF-kBsignalling (Leitges, M., Sanz, L., Martin, P., Duran, A., Braun, U.,Garcia, J. F., Camacho, F., Diaz-Meco, M. T., Rennert, P. D., andMoscat, J. (2001). Targeted disruption of the zetaPKC gene results inthe impairment of the NF-kappaB pathway. Mol Cell 8, 771-780), and PKCιin insulin secretion and action (Farese, R. V., Sajan, M. P., Yang, H.,Li, P., Mastorides, S., Gower, W. R., Jr., Nimal, S., Choi, C. S., Kim,S., Shulman, G. I., et al. (2007). Muscle-specific knockout ofPKC-lambda impairs glucose transport and induces metabolic and diabeticsyndromes. J Clin Invest 117, 2289-2301). In addition, both isoformshave been implicated in the pathogenesis of cancer making a strong casefor the inhibition of the aPKCs as a novel therapeutic avenue.

PKCι is a known oncogene in non-small cell lung cancer (NSCLC). In onestudy it was shown to be overexpressed in 69% of NSCLC cases at theprotein level. Consistent with this, the PKCι gene (PRKCI residing onchromosome 3q26) was shown to be amplified in 36.5% of NSCLC tumoursexamined, including 96% of the squamous cell carcinoma sub-type (Regala,R. P., Weems, C., Jamieson, L., Khoor, A., Edell, E. S., Lohse, C. M.,and Fields, A. P. (2005b). Atypical protein kinase C iota is an oncogenein human non-small cell lung cancer. Cancer Res 65, 8905-8911).Amplification of 3q26 has also been reported in 44% of ovarian cancers,including >70% of serous epithelial ovarian cancers where 3q26amplification is translated into increased PKCι protein expression.Moreover, increased PKCι expression is associated with poor prognosis inNSCLC and ovarian cancer where it may serve as a diagnostic biomarker ofaggressive disease (Eder, A. M., Sui, X., Rosen, D. G., Nolden, L. K.,Cheng, K. W., Lahad, J. P., Kango-Singh, M., Lu, K. H., Warneke, C. L.,Atkinson, E. N., et al. (2005). Atypical PKCiota contributes to poorprognosis through loss of apical-basal polarity and cyclin Eoverexpression in ovarian cancer. Proc Natl Acad Sci USA 102,12519-12524; Zhang, L., Huang, J., Yang, N., Liang, S., Barchetti, A.,Giannakakis, A., Cadungog, M. G., O'Brien-Jenkins, A., Massobrio, M.,Roby, K. F., et al. (2006). Integrative genomic analysis of proteinkinase C (PKC) family identifies PKCiota as a biomarker and potentialoncogene in ovarian carcinoma. Cancer Res 66, 4627-4635). 3q26amplifications have been observed in many other cancers includingoesophageal squamous cell carcinoma (Yang, Y. L., Chu, J. Y., Luo, M.L., Wu, Y. P., Zhang, Y., Feng, Y. B., Shi, Z. Z., Xu, X., Han, Y. L.,Cai, Y., et al. (2008). Amplification of PRKCI, located in 3q26, isassociated with lymph node metastasis in esophageal squamous cellcarcinoma. Genes Chromosomes Cancer 47, 127-136) and breast cancer(Kojima, Y., Akimoto, K., Nagashima, Y., Ishiguro, H., Shirai, S.,Chishima, T., Ichikawa, Y., Ishikawa, T., Sasaki, T., Kubota, Y., et al.(2008). The overexpression and altered localization of the atypicalprotein kinase C lambda/iota in breast cancer correlates with thepathologic type of these tumors. Hum Pathol 39, 824-831) suggesting thatPKCι may also participate in the pathogenesis of these diseases.

In NSCLC the primary function of PKCι is to drive transformed growth viaa Rac1/PAK/MEK/ERK signalling axis. However, PKCι also functions inNSCLC survival, resistance to chemotherapy, and invasion via distinctpathways (reviewed in Fields, A. P., and Regala, R. P. (2007). Proteinkinase C iota: human oncogene, prognostic marker and therapeutic target.Pharmacol Res 55, 487-497). In ovarian cancer transformed growth iscorrelated with deregulated epithelial cell polarity and increased cycleE expression (Eder et al., 2005) suggesting that PKCι can influence thecancer phenotype through multiple mechanisms. Compelling evidence hasemerged to suggest that inhibition of PKCι may be a useful therapeuticapproach to combat tumours characterised by increased PKCι expression.In transgenic models, mice with elevated PKCι activity in the colon aremore susceptible to carcinogen-induced colon carcinogenesis, andexpression of a kinase-dead mutant of PKCι blocks the transformation ofintestinal cells by oncogenic Ras (Murray, N. R., Jamieson, L., Yu, W.,Zhang, J., Gokmen-Polar, Y., Sier, D., Anastasiadis, P., Gatalica, Z.,Thompson, E. A., and Fields, A. P. (2004). Protein kinase Ciota isrequired for Ras transformation and colon carcinogenesis in vivo. J CellBiol 164, 797-802). Finally, genetic or pharmacological inhibition ofPKCι by a gold derivative—aurothiomalate (ATM)—blocks the growth ofNSCLC cells in soft agar and significantly decreases tumour volume inxenograft models of NSCLC (Regala, R. P., Thompson, E. A., and Fields,A. P. (2008). Atypical protein kinase C iota expression andaurothiomalate sensitivity in human lung cancer cells. Cancer Res 68,5888-5895; Regala, R. P., Weems, C., Jamieson, L., Copland, J. A.,Thompson, E. A., and Fields, A. P. (2005a). Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth andtumorigenicity. J Biol Chem 280, 31109-31115).

Despite the high degree of similarity between aPKC isoforms, the role ofPKC in cancer is distinct from that of PKCι. PKC plays a role in NSCLCcell survival by phosphorylating and antagonising the pro-apoptoticeffects of Bax in response to nicotine (Xin, M., Gao, F., May, W. S.,Flagg, T., and Deng, X. (2007). Protein kinase Czeta abrogates theproapoptotic function of Bax through phosphorylation. J Biol Chem 282,21268-21277). PKC activity has also been linked to resistance against awide range of cytotoxic and genotoxic agents. For instance, in humanleukaemia cells, overexpression of PKC confers resistance against1-β-D-arabinofuranosylcytosine (ara-C), daunorubicin, etoposide, andmitoxantrone-induced apoptosis (Filomenko, R., Poirson-Bichat, F.,Billerey, C., Belon, J. P., Garrido, C., Solary, E., and Bettaieb, A.(2002). Atypical protein kinase C zeta as a target forchemosensitization of tumor cells. Cancer Res 62, 1815-1821; Plo, I.,Hernandez, H., Kohlhagen, G., Lautier, D., Pommier, Y., and Laurent, G.(2002). Overexpression of the atypical protein kinase C zeta reducestopoisomerase II catalytic activity, cleavable complexes formation, anddrug-induced cytotoxicity in monocytic U937 leukemia cells. J Biol Chem277, 31407-31415). Furthermore, inhibition of PKC activity throughexpression of a kinase-dead mutant sensitizes leukaemia cells to thecytotoxic effects of etoposide both in vitro and in vivo (Filomenko etal., 2002). Atypical protein kinase C regulates dual pathways fordegradation of the oncogenic coactivator SRC-3/AIB1. Mol Cell 29,465-476), and both of these proteins have been postulated to play a rolein tamoxifen resistance in breast cancer (Iorns, E., Lord, C. J., andAshworth, A. (2009). Parallel RNAi and compound screens identify thePDK1 pathway as a target for tamoxifen sensitization. Biochem J 417,361-370; Osborne, C. K., Bardou, V., Hopp, T. A., Chamness, G. C.,Hilsenbeck, S. G., Fuqua, S. A., Wong, J., Allred, D. C., Clark, G. M.,and Schiff, R. (2003). Role of the estrogen receptor coactivator AIB1(SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J NatlCancer Inst 95, 353-361). Together these studies suggest that inhibitionof PKC activity may have beneficial therapeutic effects by acting as achemosensitiser to a wide array of commonly used chemotoxic agents inthe clinic.

Further evidence that small molecule inhibition of PKC could haveimportant therapeutic benefits has recently emerged from tumour modelsthat link PKC signalling to the mTOR pathway. PKC is constitutivelyactivated in follicular lymphoma and has been identified as a noveltarget for the anti-CD20 therapeutic antibody rituximab (Leseux, L.,Laurent, G., Laurent, C., Rigo, M., Blanc, A., Olive, D., and Bezombes,C. (2008). PKC zeta mTOR pathway: a new target for rituximab therapy infollicular lymphoma. Blood 111, 285-291). Rituximab inhibits follicularlymphoma proliferation by targeting a PKCζ-MAPK-mTOR pathway, suggestingthat PKC is both a target of Rituximab, and a key regulator of its'anti-leukaemic effect. Regulation of the mTOR/p70S6K pathway by PKC hasalso been implicated in the transition of prostate cancer cells to anandrogen-independent state (Inoue, T., Yoshida, T., Shimizu, Y.,Kobayashi, T., Yamasaki, T., Toda, Y., Segawa, T., Kamoto, T., Nakamura,E., and Ogawa, O. (2006). Requirement of androgen-dependent activationof protein kinase Czeta for androgen-dependent cell proliferation inLNCaP Cells and its roles in transition to androgen-independent cells.Mol Endocrinol 20, 3053-3069). Finally, mice containing a homozygousdeletion of Par4, a negative regulator of PKC, exhibit greatly enhancedPKC activity. These mice spontaneously develop tumours of the prostateand endometrium, and potentiate Ras-induced lung carcinogenesisconsistent with a role for PKC in lung cancer (Garcia-Cao, I., Duran,A., Collado, M., Carrascosa, M. J., Martin-Caballero, J., Flores, J. M.,Diaz-Meco, M. T., Moscat, J., and Serrano, M. (2005). Tumour-suppressionactivity of the proapoptotic regulator Par4. EMBO Rep 6, 577-583; Joshi,J., Fernandez-Marcos, P. J., Galvez, A., Amanchy, R., Linares, J. F.,Duran, A., Pathrose, P., Leitges, M., Canamero, M., Collado, M., et al.(2008). Par-4 inhibits Akt and suppresses Ras-induced lungtumorigenesis. EMBO J 27, 2181-2193).

A need exists for aPKC inhibitors for use as pharmaceutical agents.

SUMMARY OF THE INVENTION

The invention provides a compound of formula (I)

or a salt thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, A, G, M, Q and X areas defined herein.

A compound of formula (I) and its salts have aPKC inhibitory activity,and may be used to treat aPKC-dependent disorders or conditions.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with at least one pharmaceutically acceptablecarrier, diluent, or excipient therefor.

In another aspect, the present invention provides a method of treating asubject suffering from an aPKC-dependent disorder or conditioncomprising: administering to the subject a compound of formula (I) or apharmaceutically acceptable salt thereof.

The present invention further provides a method of treating aproliferative disorder in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“About” as used herein when referring to a measurable value such as anamount, a temporal duration, and the like, is meant to encompassreasonable variations of the value, such as, for example, +10% from thespecified value. For example, the phrase “about 50” encompassesreasonable variations of 50, such as +10% of the numerical value 50, orfrom 45 to 55.

“Alkyl” or “alkyl group” refers to a monoradical of a branched orunbranched saturated hydrocarbon chain. Examples include, but are notlimited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl,etc. Alkyl groups typically contain 1-10 carbon atoms, such as 1-6carbon atoms or 1-4 carbon atoms, and can be substituted orunsubstituted.

“Alkylene” or “alkylene group” refers to a diradical of a branched orunbranched saturated hydrocarbon chain. Examples include, but are notlimited to, methylene (—CH₂—), the ethylene isomers (—CH(CH₃)— and—CH₂CH₂—), the propylene isomers (—CH(CH₃)CH₂—, —CH(CH₂CH₃)—, —C(CH₃)₂—,and —CH₂CH₂CH₂—), etc. Alkylene groups typically contain 1-10 carbonatoms, such as 1-6 carbon atoms, and can be substituted orunsubstituted.

“Alkenyl” or “alkenyl group” refers to a monoradical of a branched orunbranched hydrocarbon chain containing at least one double bond.Examples include, but are not limited to, ethenyl, 3-buten-1-yl,2-ethenylbutyl, and 3-hexen-1-yl. Alkenyl groups typically contain 2-10carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can besubstituted or unsubstituted.

“Alkynyl” or “alkynyl group” refers to a monoradical of a branched orunbranched hydrocarbon chain containing at least one triple bond.Examples include, but are not limited to, ethynyl, 3-butyn-1-yl,propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl. Alkynyl groups typicallycontain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms,and can be substituted or unsubstituted.

“Aryl” or “aryl group” refers to phenyl and 7-15 membered monoradicalbicyclic or tricyclic hydrocarbon ring systems, including bridged,spiro, and/or fused ring systems, in which at least one of the rings isaromatic. Aryl groups can be substituted or unsubstituted. Examplesinclude, but are not limited to, naphthyl, indanyl,1,2,3,4-tetrahydronaphthalenyl,6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and6,7,8,9-tetrahydro-5H-benzocycloheptenyl. An aryl group may contain 6(i.e., phenyl) or 9 to 15 ring atoms, such as 6 (i.e., phenyl) or 9-11ring atoms, e.g., 6 (i.e., phenyl), 9 or 10 ring atoms.

“Arylene” or “arylene group” refers to a phenylene (—C₆H₄—) or a 7-15membered diradical bicyclic or tricyclic hydrocarbon ring systems,including bridged, spiro, and/or fused ring systems, in which at leastone of the rings is aromatic. Arylene groups can be substituted orunsubstituted. For example, an arylene group may contain 6 (i.e.,phenylene) or 9 to 15 ring atoms; such as 6 (i.e., phenylene) or 9-11ring atoms; e.g., 6 (i.e., phenylene), 9 or 10 ring atoms. An arylenegroup can also include ring systems substituted on ring carbons with oneor more —OH functional groups (which may further tautomerize to give aring C═O group).

“Arylalkyl” or “arylalkyl group” refers to an alkyl group in which ahydrogen atom is replaced by an aryl group, wherein alkyl group and arylgroup are as previously defined (i.e., arylalkyl-). Arylalkyl groups canbe substituted or unsubstituted. Examples include, but are not limitedto, benzyl (C₆H₅CH₂—).

“Cycloalkyl” or “cycloalkyl group” refers to a monoradical non-aromaticcarbocyclic ring system, which may be saturated or unsaturated,substituted or unsubstituted, and may be monocyclic, bicyclic, ortricyclic, and may be bridged, spiro, and/or fused. Examples include,but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl,cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane,bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[3.3.2]decane. The cycloalkyl group may contain from 3 to 10 ringatoms, such as 3 to 7 ring atoms (e.g., 3 ring atoms, 5 ring atoms, 6ring atoms, or 7 ring atoms).

“Cycloalkylalkyl” or “cycloalkylalkyl group” refers to an alkyl group inwhich a hydrogen atom is replaced by a cycloalkyl group, wherein alkylgroup and cycloalkyl group are as previously defined (i.e.,cycloalkylalkyl-). Cycloalkylalkyl groups can be substituted orunsubstituted. Examples include, but are not limited to,cyclohexylmethyl (C₆H₁₁CH₂—).

“Haloalkyl” or “haloalkyl group” refers to alkyl groups in which one ormore hydrogen atoms are replaced by halogen atoms. Haloalkyl includesboth saturated alkyl groups and unsaturated alkenyl and alkynyl groups,such as for example —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃,—CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂,—CI═CH₂, —C≡C≡CF₃, —CHFCH₂CH₃ and —CHFCH₂CF₃.

“Halogen” includes fluorine, chlorine, bromine and iodine atoms.

“Heteroaryl” or “heteroaryl group” refers to (a) 5 and 6 memberedmonocyclic aromatic rings, which contain, in addition to carbon atom(s),at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b)7-15 membered bicyclic and tricyclic rings, which contain, in additionto carbon atom(s), at least one heteroatom, such as nitrogen, oxygen orsulfur, and in which at least one of the rings is aromatic. Heteroarylgroups can be substituted or unsubstituted, and may be bridged, spiro,and/or fused. Examples include, but are not limited to,2,3-dihydrobenzofuranyl, 1,2-dihydroquinolinyl,3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl,furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl,2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl,pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl,2-thienyl, 3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl,triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl,pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl,alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl,2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl,benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl,indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl,quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl,10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trienyl,12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trienyl,12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trienyl,10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trienyl,2,3,4,5-tetrahydro-1H-benzo[d]azepinyl,1,3,4,5-tetrahydro-benzo[d]azepin-2-onyl,1,3,4,5-tetrahydro-benzo[b]azepin-2-onyl,2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl,1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-onyl,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl,5,6,8,9-tetrahydro-7-oxa-benzocycloheptenyl,2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,1,2,4,5-tetrahydro-benzo[e][1,3]diazepin-3-onyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl,6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl,5,5-dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and2,3,4,5-tetrahydro-benzo[f][1,4]oxazepinyl. For example, a heteroarylgroup may contain 5, 6, or 8-15 ring atoms. As another example, aheteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10ring atoms.

“Heteroarylalkyl” or “heteroarylalkyl group” refers to an alkyl group inwhich a hydrogen atom is replaced by a heteroaryl group, wherein alkylgroup and heteroaryl group are as previously defined (i.e.,heteroarylalkyl-). Heteroarylalkyl groups can be substituted orunsubstituted. Examples include, but are not limited to, thepyridinylmethyl isomers

“Heterocycloalkyl” or “heterocycloalkyl group” refers to 3-15 memberedmonocyclic, bicyclic, and tricyclic non-aromatic rings, which may besaturated or unsaturated, can be substituted or unsubstituted, may bebridged, spiro, and/or fused, and which contain, in addition to carbonatom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur orphosphorus. Examples include, but are not limited to, tetrahydrofuranyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl,morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl,homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide,pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl,homopiperidinyl, homothiomorpholinyl-S, S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-5-oxide, quinuclidinyl,2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-aza-bicyclo[3.2.1]octane,3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane,3,8-diaza-bicyclo[3.2.1]octane, 3,9-diaza-bicyclo[4.2.1]nonane,2,6-diaza-bicyclo[3.2.2]nonane, [1,4]oxaphosphinane 4-oxide,[1,4]azaphosphinane 4-oxide, [1,2]oxaphospholane 2-oxide, phosphinane1-oxide, [1,3]azaphospholidine 3-oxide, and [1,3]oxaphospholane 3-oxide.A heterocycloalkyl group may contain, in addition to carbon atom(s), atleast one nitrogen, oxygen, or sulfur. For example, a heterocycloalkylgroup may contain, in addition to carbon atom(s), at least one nitrogenor oxygen. A heterocycloalkyl group may contain, in addition to carbonatom(s), at least one nitrogen. A heterocycloalkyl group may containfrom 3 to 10 ring atoms. A heterocycloalkyl group may contain from 3 to7 ring atoms. A heterocycloalkyl group may contain from 5 to 7 ringatoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Unlessotherwise indicated, the foregoing heterocycloalkyl groups can beC-attached or N-attached where such is possible and results in thecreation of a stable structure. For example, piperidinyl can bepiperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).

“Heterocycloalkylene” or “heterocycloalkylene group” refers todiradical, 3-15 membered monocyclic, bicyclic, or tricyclic non-aromaticring systems, which may be saturated or unsaturated, can be substitutedor unsubstituted, may be bridged, spiro, and/or fused, and whichcontain, in addition to carbon atom(s), at least one heteroatom, such asnitrogen, oxygen, sulfur or phosphorus. Examples include, but are notlimited to, the azridinylene isomers

The heterocycloalkylene group may contain, in addition to carbonatom(s), at least one nitrogen, oxygen, or sulfur. Theheterocycloalkylene group may contain, in addition to carbon atom(s), atleast one nitrogen or oxygen. The heterocycloalkylene group may contain,in addition to carbon atom(s), at least one nitrogen. For example, aheterocycloalkylene group may contain from 3 to 10 ring atoms; such asfrom 3 to 7 ring atoms. A heterocycloalkylene group may contain from 5to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.Unless otherwise indicated, the foregoing heterocycloalkylene groups canbe C-attached and/or N-attached where such is possible and results inthe creation of a stable structure. A heterocycloalkylene group can alsoinclude ring systems substituted on ring carbons with one or more —OHfunctional groups (which may further tautomerize to give a ring C═Ogroup) and/or substituted on a ring sulfur atom by one (1) or two (2)oxygen atoms to give S═O or SO₂ groups, respectively, and/or substitutedon a ring phosphorus by an oxygen atom to give P═O.

“Heterocycloalkylalkyl” or “heterocycloalkylalkyl group” refers to analkyl group in which a hydrogen atom is replaced by a heterocycloalkylgroup, wherein alkyl group and heterocycloalkyl group are as previouslydefined (i.e., heterocycloalkylalkyl-). Heteroycloalkylalkyl groups canbe substituted or unsubstituted. Examples include, but are not limitedto, pyrrolidinylmethyl (C₄H₈NCH₂—).

“Pharmaceutically acceptable” refers to physiologically tolerablematerials, which do not typically produce an allergic or other untowardreaction, such as gastric upset, dizziness and the like, whenadministered to a human.

“Pharmaceutical composition” refers to a composition that can be used totreat a disease, condition, or disorder in a human.

“Pseudohalogen” refers to —OCN, —SCN, —CF₃, and —CN.

“Stable” or “chemically stable” refers to a compound that issufficiently robust to be isolated to a useful degree of purity from areaction mixture. The present invention is directed solely to thepreparation of stable compounds. When lists of alternative substituentsinclude members which, owing to valency requirements, chemicalstability, or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read in context to include thosemembers of the list that are suitable for substituting the particulargroup. For example, R¹ can be C₁₋₆alkyl optionally substituted by 1-13R¹⁹; when R¹ is methyl, the methyl group is optionally substituted by1-3 R¹⁹.

“Therapeutically effective amount” refers to an amount of a compoundsufficient to inhibit, halt, or cause an improvement in a disorder orcondition being treated in a particular subject or subject population.For example in a human or other mammal, a therapeutically effectiveamount can be determined experimentally in a laboratory or clinicalsetting, or may be the amount required by the guidelines of the UnitedStates Food and Drug Administration, or equivalent foreign agency, forthe particular disease and subject being treated. It should beappreciated that determination of proper dosage forms, dosage amounts,and routes of administration is within the level of ordinary skill inthe pharmaceutical and medical arts.

“Treatment” refers to the acute or prophylactic diminishment oralleviation of at least one symptom or characteristic associated orcaused by a disorder being treated. For example, treatment can includediminishment of several symptoms of a disorder or complete eradicationof a disorder.

II. Compounds

The compounds of the present invention are defined by the followingnumbered Embodiments. When a higher numbered Embodiment refers back tomultiple previous lower numbered Embodiments in the alternative andcontains a new limitation not present in the lower numbered Embodiments,the higher numbered Embodiment is intended to be an express descriptionof each and every one of the alternatives. For example, if Embodiment 2refers back to Embodiment 1 and contains a limitation not present inEmbodiment 1, Embodiment 3 refers back Embodiments 1 or 2 and contains alimitation(s) not present in Embodiments 1 or 2, and Embodiment 4 refersback to any of Embodiments 1-3 and contains a limitation(s) not presentin Embodiments 1, 2 or 3, then Embodiment 4 is intended to be anexplicit description of a genus having the limitations of Embodiments 1and 4, an explicit description of a genus having the limitations ofEmbodiments 1, 2 and 4, an explicit description of a genus having thelimitations of Embodiments 1, 3 and 4, and an explicit description of agenus having the limitations of Embodiments 1, 2, 3 and 4. By way ofexample, if Embodiment 1 is a compound of formula (I) defining R¹, R²and R³ independently as alkyl or aryl, and Embodiment 2 is a compound ofEmbodiment 1 defining R¹ as alkyl, and Embodiment 3 is a compound ofEmbodiments 1 or 2 defining R² as alkyl, and Embodiment 4 is a compoundof any of Embodiments 1-3 defining R³ as alkyl, then Embodiment 4 is anexplicit description of a genus having the limitations of Embodiments 1and 4 (i.e., a compound of formula (I) in which R¹ and R² are alkyl oraryl, and R³ is alkyl), an explicit description of a genus having thelimitations of Embodiments 1, 2 and 4 (i.e., a compound of formula (I)in which R² is alkyl or aryl, and R¹ and R³ are alkyl), an explicitdescription of a genus having the limitations of Embodiments 1, 3 and 4(i.e., a compound of formula (I) in which R¹ is alkyl or aryl, and R²and R³ are alkyl), and an explicit description of a genus having thelimitations of Embodiments 1, 2, 3 and 4 (i.e., a compound of formula(I) in which R¹, R² and R³ are alkyl). It should be noted in this regardthat when a higher numbered Embodiment refers to a lower numberedEmbodiment and contains limitations for a group(s) not present in thelower numbered Embodiment, the higher numbered Embodiment should beinterpreted in context to ignore the missing group(s). For example, ifEmbodiment 1 recites a compound of formula (I) in which A is NR¹¹, O, orS, Embodiment 2 recites a compound of Embodiment 1 in which A is O or S,and

Embodiment 3 recites a compound of Embodiments 1 or 2 in which R¹¹ isalkyl, then Embodiment 3 defines a genus having the limitations ofEmbodiments 1 and 3 and a genus having the limitation of Embodiments 1,2 and 3. In the genus defined by the limitations of Embodiments 1, 2 and3, A cannot be NR¹¹; therefore this genus should be interpreted toignore and omit the Embodiment 3 definition of R¹¹=alkyl.

Embodiment 1

A compound of formula (I)

or a salt form thereof,wherein

-   -   A is NR¹¹, O, or S;    -   M-Q-X is a group of formula

-   -   G is a group of formula

-   -   R¹, R², R¹¹, and R¹⁷ are independently chosen from H, C₁₋₆alkyl        optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by        1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹, and —OR²⁰;    -   R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R⁵, R¹⁶, and R¹⁸        are independently chosen from H, C₁₋₆alkyl optionally        substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by        1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,        C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl        optionally substituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally        substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyl optionally        substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyl        optionally substituted by 1-28 R¹⁹, 4-21 membered        heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15        membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21        membered heteroarylalkyl optionally substituted by 1-27 R¹⁹,        halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³,        —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³,        —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰,        —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,        —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,        —NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(═NR²⁵)NR²²R²³,        —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰,        —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,        —NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³),        —NR²⁴P(═)(OR²⁰)(OR²⁰), —NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN,        —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³,        —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,        —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³), —OP(═O)(OR²⁰)(OR²⁰),        —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²,        —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —SP(═O)R²⁸R²⁸,        —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),        —SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),        —P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰);    -   any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹,        R⁶ and R¹¹, and R¹⁶ and R¹⁷ can, together with the atoms linking        them, form a 3-15 membered heterocycloalkyl optionally        substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionally        substituted by 1-15 R¹⁹;    -   any of R³ and R⁶, R⁷ and R⁸, R⁹ and R¹⁰, R¹² and R¹³, and R¹⁴        and R¹⁵ can, together with the atoms linking them, form a        C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl        optionally substituted by 1-21 R¹⁹, 3-15 membered        heterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15        membered heteroaryl optionally substituted by 1-15 R¹⁹;    -   R³ and R⁵ or R⁴ and R⁶ can together form a double bond;    -   any of R³ and R⁴, and R⁵ and R⁶ can together form ═O, ═NR²⁰,        ═NOR²⁰, or ═S;    -   R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R³⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R³⁹, C₂₋₆alkynyl optionally substituted by        1-9 R³⁹, C₆₋₁₁aryl optionally substituted by 1-11 R³⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R³⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R³⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R³⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R³⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R³⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R³⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³,        —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰, —C(═NR³⁵)NR³²R³³, —C(═NOH)NR³²R³³,        —C(═NOR³⁶)R³⁰, —C(═NR³²R³³)R³⁰, —C(═NNR³⁴C(═O)R³¹)R³⁰,        —C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂, —NR³²R³³,        —NR³⁴NR³²R³³, —N═NR³⁴, ═NR³⁰, ═NOR³⁰, —NR³⁴R³⁶, —NR³⁴C(═O)R³⁰,        —NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,        —NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰,        —NR³⁴C(═O)NR³⁴C(═O)OR³⁰, —NR³⁴C(═NR³⁵)NR³²R³³,        —NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴C(═S)R³⁰, —NR³⁴C(═S)OR³⁰,        —NR³⁴C(═S)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,        —NR³⁴P(═O)R³⁸R³⁸, —NR³⁴P(═O)(NR³²R³³)(NR³²R³³),        —NR³⁴P(═O)(OR³⁰)(OR³⁰), —NR³⁴P(═O)(SR³⁰)(SR³⁰), —OR³⁰, ═O, —OCN,        —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,        —OS(═O)R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂NR³²R³³,        —OP(═O)R³⁸R³⁸, —OP(═O)(NR³²R³³)(NR³²R³³), —OP(═O)(OR³⁰)(OR³⁰),        —OP(═O)(SR³⁰)(SR³⁰), —Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰,        —S(═O)₂OR³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,        —SP(═O)R³⁸R³⁸, —SP(═O)(NR³²R³³)(NR³²R³³), —SP(═O)(OR³⁰)(OR³⁰),        —SP(═O)(SR³⁰)(SR³⁰), —P(═O)R³⁸R³⁸, —P(═O)(NR³²R³³)(NR³²R³³),        —P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰);    -   R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at        each occurrence is independently chosen from H, C₁₋₆alkyl        optionally substituted by 1-13 R⁴⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R⁴⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁴⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁴⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁴⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁴⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁴⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁴⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁴⁹;    -   R²⁸ and R³⁸ at each occurrence is independently chosen from        C₁₋₆alkyl optionally substituted by 1-13 R⁴⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁴⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁴⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁴⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁴⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁴⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁴⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁴⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁴⁹,    -   R²², R²³, R³² and R³³ at each occurrence is independently chosen        from H, C₁₋₆alkyl optionally substituted by 1-13 R⁵⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁵⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁵⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁵⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁵⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁵⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁵⁹; or any R²² and R²³ and/or R³² and R³³        may form, together with the nitrogen atom to which they are        attached, a 3-15 membered heterocycloalkyl optionally        substituted by 1-28 R⁶⁹ or a 5-15 membered heteroaryl optionally        substituted by 1-15 R⁶⁹;    -   R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen        from C₁₋₆alkyl optionally substituted by 1-13 R⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁷⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁷⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁷⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³,        —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰, —C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³,        —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰, —C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰,        —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³,        —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴R⁷⁶, —NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═O)OR⁷¹,        —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰, —NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³,        —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰, —NR⁷⁴C(═S)OR⁷⁰,        —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,        —NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —NR⁷⁴P(═O)(OR⁷⁰)(OR⁷⁰), —NR⁷⁴P(═)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, ═O, —OCN,        —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³,        —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —OP(═O)(OR⁷⁰)(OR⁷⁰),        —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S, —S(═O)_(n)R⁷⁰,        —S(═O)₂R⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),        —SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰);    -   R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁸⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R⁸⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R⁸⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R⁸⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R⁸⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32        R⁸⁹, 3-15 membered heterocycloalkyl optionally substituted by        1-28 R⁸⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R⁸⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R⁸⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R⁸⁹;    -   R⁷² and R⁷³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R⁹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁹⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁹⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁹⁹; or any R⁷² and R⁷³ may form, together        with the nitrogen atom to which they are attached, a 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁰⁹ or        a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁰⁹;    -   R⁷⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R⁸⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R⁸⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁸⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁸⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁸⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁸⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R⁸⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁸⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁸⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁸⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁸⁹;    -   R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 halogen,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl,        C₃₋₁₁cycloalkyl, C₄₋₁₇cycloalkylalkyl, 3-15 membered        heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15        membered heteroaryl, 6-21 membered heteroarylalkyl, halogen,        —CN, —C(═O)R¹¹⁰, —C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —C(═O)C(═O)R¹¹⁰,        —C(═NR¹¹⁰)R¹¹⁰, —C(═NR¹¹⁰)NR¹¹⁰R¹¹⁰, —C(═NOH)NR¹¹R¹¹⁰,        —C(═NOR¹¹⁰)R¹¹⁰, —C(═NNR¹¹⁰R¹¹⁰)R¹¹⁰, —C(═NNR¹¹⁰C(═O)R¹¹⁰)R¹¹⁰,        —C(═NNR¹¹⁰C(═O)OR¹¹⁰)R¹¹⁰, —C(═S)NR¹¹⁰R¹¹⁰, —NC, —NO₂,        —NR¹¹R¹¹⁰, —NR¹¹⁰NR¹¹⁰R¹¹⁰, —N═NR¹¹⁰, ═NR¹¹⁰, ═NOR¹¹⁰,        —NR¹¹⁰OR¹¹⁰, —NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)C(═O)R¹¹⁰,        —NR¹¹⁰C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰,        —NR¹¹⁰C(═O)NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰C(═O)OR¹¹⁰,        —NR¹¹⁰C(═NR¹¹⁰)NR¹¹⁰R¹¹⁰, —NR¹¹⁰C(═O)C(═O)NR¹¹⁰R¹¹⁰,        —NR¹¹⁰C(═S)R¹¹⁰, —NR¹¹⁰C(═S)OR¹¹⁰, —NR¹¹⁰C(═S)NR¹¹⁰R¹¹⁰,        —NR¹¹⁰S(═O)₂R¹¹⁰, —NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰, —NR¹¹⁰P(═O)R¹¹¹R¹¹¹,        —NR¹¹⁰P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —NR¹¹⁰P(═O)(OR¹¹⁰)(OR¹¹⁰),        —NR¹¹⁰P(═O)(SR¹¹⁰)(SR¹¹⁰), —OR¹¹⁰, ═O, —OCN, —OC(═O)R¹¹⁰,        —OC(═O)NR¹¹⁰R¹¹⁰, —OC(═O)OR¹¹⁰, —OC(═NR¹¹⁰)NR¹¹⁰R¹¹⁰,        —OS(═O)R¹¹⁰, —OS(═O)₂R¹¹⁰, —OS(═O)₂OR¹¹⁰, —OS(═O)₂NR¹¹⁰R¹¹⁰,        —OP(═O)R¹¹¹R¹¹¹, —OP(═O)(NR¹¹⁰OR¹¹⁰)(NR¹¹⁰OR¹¹⁰),        —OP(═O)(OR¹¹⁰)(OR¹¹⁰), —OP(═O)(SR¹¹⁰)(SR¹¹⁰), —Si(R¹¹⁰)₃, —SCN,        ═S, —S(═O)_(n)R¹¹⁰, —S(═O)₂OR¹¹⁰, —SO₃R¹¹⁰, —S(═O)₂NR¹¹⁰R¹¹⁰,        —S(═O)NR¹¹⁰R¹¹⁰, —SP(═O)R¹¹¹R¹¹¹, —SP(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰),        —SP(═O)(OR¹¹⁰)(OR¹¹⁰), —SP(═O)(SR¹¹⁰)(SR¹¹⁰), —P(═O)R¹¹⁰R¹¹⁰,        —P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —P(═O)(OR¹¹⁰)(OR¹¹⁰), and        —P(═O)(SR¹¹⁰)(SR¹¹⁰);    -   R¹¹⁰ at each occurrence is independently chosen from H,        C₁₋₆alkyl and C₁₋₆-haloalkyl;    -   R¹¹¹ at each occurrence is independently chosen from C₁₋₆alkyl        and C₁₋₆-haloalkyl; and    -   n at each occurrence is independently chosen from 0, 1, and 2.

Embodiment 2

The compound of Embodiment 1, wherein A is NR¹¹, O, or S.

Embodiment 3

The compound of Embodiment 1, wherein A is NR¹¹ or O.

Embodiment 4

The compound of Embodiment 1, wherein A is NR¹¹.

Embodiment 5

The compound of Embodiment 1, wherein A is O.

Embodiment 5

The compound of Embodiment 1, wherein A is S.

Embodiment 6

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

Embodiment 7

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

and the compound of formula (I) is a compound of formula (Ia)

Embodiment 8

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

and the compound of formula (I) is a compound of formula (Ib)

Embodiment 9

The compound of any of Embodiments 1-8, wherein G is a group of formula

Embodiment 10

The compound of any of Embodiments 1-8, wherein G is a group of formula

Embodiment 11

The compound of any of Embodiments 1-8, wherein G is a group of formula

and the compound of formula (I) is a compound of formula (Ic)

Embodiment 12

The compound of any of Embodiments 1-8, wherein G is a group of formula

and the compound of formula (I) is a compound of formula (Id)

Embodiment 13

The compound of any of Embodiments 1-8, wherein G is a group of formula

and the compound of formula (I) is a compound of formula (Ie)

Embodiment 14

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

G is a group of formula

and the compound of formula (I) is a compound of formula (If)

Embodiment 15

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

G is a group of formula

and the compound of formula (I) is a compound of formula (Ig)

Embodiment 16

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

G is a group of formula

and the compound of formula (I) is a compound of formula (Ih)

Embodiment 17

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

G is a group of formula

and the compound of formula (I) is a compound of formula (Ii)

Embodiment 18

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

G is a group of formula

and the compound of formula (I) is a compound of formula (Ij)

Embodiment 19

The compound of any of Embodiments 1-5, wherein M-Q-X is a group offormula

G is a group of formula

and the compound of formula (I) is a compound of formula (Ik)

Embodiment 20

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁-aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, and —OR²⁰; R³, R⁴, R⁵, and R⁶ are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₆₋₁₁-aryl optionally substituted by 1-11 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₃₋₁₁-cycloalkyloptionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyl optionallysubstituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³,—C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³,—C(═NOR²⁶)R²⁰, —C(═NR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰,—C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)R²¹,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(NR²⁵)NR²²R²³,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰,—NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —NR²⁴P(═O)R²⁸R²⁸,—NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R²⁸R²⁸, —SP(═O)(NR²²23)(NR²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰); alternatively, R³ and R⁶can, together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹;alternatively R³ and R⁵ or R⁴ and R⁶ can together form a double bond;alternatively any of R³ and R⁴, and R⁵ and R⁶ can together form ═O,═NR²⁰, ═NOR²⁰, or ═S; and alternatively any of R¹ and R², R¹ and R³, R¹and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, together with theatoms linking them, form a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹.

Embodiment 21

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, and —OR²⁰; R³, R⁴, R⁵, and R⁶ are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-32 R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R¹⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰,—C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NR²²R²³)R²⁰,—C(═NNR²⁴C(═O)R)R¹)R²⁰, —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC,—NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³R²², —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²),—NR²⁴P(═)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(R²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²,—S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —SP(═O)R²⁸R²⁸,—SP(═O)((NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰), —SP(═O)(SR²⁰)(SR²⁰),—P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³)C, —P(═O)(OR²⁰)(OR²⁰), and—P(═O)(SR²⁰)(SR²⁰); alternatively, R³ and R⁶ can, together with theatoms linking them, form a C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹; alternatively R³ and R⁵

or R⁴ and R⁶ can together form a double bond; alternatively any of R³and R⁴, and R⁵ and R⁶ can together form ═O; and alternatively any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 22

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆11aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, and —OR²⁰; R³, R⁴, R⁵, and R⁶ are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹⁹, C₃11cycloalkyl optionallysubstituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-32 R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R¹⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(OR²⁰)(OR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R², —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),

and —P(═O)(OR²⁰)(OR²⁰); alternatively, R³ and R⁶ can, together with theatoms linking them, form a C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹; alternatively R³ and R⁵or R⁴ and R⁶ can together form a double bond; alternatively any of R³and R⁴, and R⁵ and R⁶ can together form ═O; and alternatively any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 23

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R¹⁹, and —OR²⁰; R³, R⁴, R⁵, and R⁶ are independentlychosen from H,

C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,—OP(═O)R²⁸R²⁸R²⁸, —OP(═O)(OR²⁰)(OR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,—S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R²⁸R²⁸,—P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); alternatively, R³ andR⁶ can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹;alternatively R³ and R⁵ or R⁴ and R⁶ can together form a double bond;alternatively any of R³ and R⁴, and R⁵ and R⁶ can together form ═O; andalternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ andR¹¹, and R⁶ and R¹¹ can, together with the atoms linking them, form a5-15 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹ or a5-15 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 24

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆11aryl optionally substituted by1-3 R¹⁹, C₇16arylalkyl optionally substituted by 1-3 R¹⁹, C₃11cycloalkyloptionally substituted by 1-3 R¹⁹, C₄₋₁₇cycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by 1-3R¹⁹, and —OR²⁰; R³, R⁴, R⁵, and R⁶ are independently chosen from H,

C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₆11aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by1-3 R¹⁹, C₄17cycloalkylalkyl optionally substituted by 1-3 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-3 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR², —OS(═O)₂NR²²R²³,—OP(═O)R²⁸R²⁸, —OP(═O)(OR²⁰)(OR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,—S(═O)₂OR², —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R²⁸R²⁸,—P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); alternatively, R³ andR⁶ can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹; alternatively R³ and R⁵ or R⁴ and R⁶ cantogether form a double bond; alternatively any of R³ and R⁴, and R⁵ andR⁶ can together form ═O; and alternatively any of R¹ and R², R¹ and R³,R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, together with theatoms linking them, form a 5-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 25

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁹, and —OR²⁰; R³,R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁-cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(OR²⁰)(OR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰);alternatively, R³ and R⁶ can, together with the atoms linking them, forma C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-3 R¹⁹; alternatively R³ and R⁵ or R⁴ and R⁶can together form a double bond; alternatively any of R³ and R⁴, and R⁵and R⁶ can together form ═O; and alternatively any of R¹ and R², R¹ andR³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, together withthe atoms linking them, form a 5-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 26

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁹, and —OR²⁰; R³,R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁-cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³; alternatively, R³ and R⁶ can, together with the atomslinking them, form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹; alternatively R³ and R⁵

or R⁴ and R⁶ can together form a double bond; alternatively any of R³and R⁴, and R⁵ and R⁶ can together form ═O; and alternatively any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹can, together with the atoms linking them, form a 5-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 27

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, and 5-15 membered heteroaryloptionally substituted by 1-3 R¹⁹; R³, R⁴, R⁵, and R⁶ are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₆₋₁₁aryloptionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, R³ and R⁶ can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹;alternatively R³ and R⁵

or R⁴ and R⁶ can together form a double bond; and alternatively any ofR¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹can, together with the atoms linking them, form a 5-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 28

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R², and —S(═O)₂NR²²R²³;alternatively, R³ and R⁶ can, together with the atoms linking them, forma C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-3 R¹⁹; alternatively R³ and R⁵ or R⁴ and R⁶can together form a double bond; and alternatively any of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, togetherwith the atoms linking them, form a 5-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 29

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R², and —S(═O)₂NR²²R²³;alternatively, any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴and R¹¹, and R⁶ and R¹¹ can, together with the atoms linking them, forma 5-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 30

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₇cycloalkyl optionally

substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, any of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, togetherwith the atoms linking them, form a 5-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹.

Embodiment 31

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, R³ and R⁶can, together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹;alternatively R³ and R⁵ or R⁴ and R⁶ can together form a double bond;and alternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴and R¹¹, and R⁶ and R¹¹ can, together with the atoms linking them, forma 5-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ or a5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 32

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹, and R⁶ and R¹¹ can,together with the atoms linking them, form a 5-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 33

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹, and R⁶ and R¹¹ can,together with the atoms linking them, form a 5-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 34

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹can, together with the atoms linking them, form a 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 35

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 36

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹can, together with the atoms linking them, form a 5-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 37

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹, and R⁶ and R¹¹ can,together with the atoms linking them, form a 5-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 38

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen from H, C₁₋₆ alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, —R²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰ and —S(═O)₂NR²²R²³; alternatively any of R¹ and R², R¹ andR³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, together withthe atoms linking them, form a 5-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 39

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁-aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁-cycloalkyl optionally substituted by 1-21 R¹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, and —OR²⁰; R³, R⁴,R⁵, and R⁶ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, C₃₋₁₁-cycloalkyl optionally substituted by 1-21 R¹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰alternatively, R³ and R⁶ can, together with the atoms linking them, forma C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-15 R¹⁹; alternatively R³ and R⁵ or R⁴ and R⁶can together form a double bond; alternatively any of R³ and R⁴, and R⁵and R⁶ can together form ═O, ═NR²⁰, ═NOR²⁰, or ═S; and alternatively anyof R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹, and R⁶ andR¹¹ can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 40

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁-aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁-cycloalkyl optionally substituted by 1-21 R¹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, and —OR²⁰; R³, R⁴,R⁵, and R⁶ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰; alternatively, R³ and R⁶ can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹;alternatively R³ and R⁵ or R⁴ and R⁶ can together form a double bond;alternatively any of R³ and R⁴, and R⁵ and R⁶ can together form ═O,═NR²⁰, ═NOR²⁰, or ═S; and alternatively any of R¹ and R², R¹ and R³, R¹and

R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹ can, together with the atomslinking them, form a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹. Embodiment 41. The compound of any ofEmbodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹ are independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-13 R¹⁹; R² ischosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-32 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; alternatively, R³ and R⁶ can, together with the atoms linkingthem, form a C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹;alternatively R³ and R⁴ can together form ═O; and alternatively any of Rand R², R and R³, R and R⁵, R and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can,together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 42

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹; R³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; alternatively, R³ and R⁶ can,together with the atoms linking them, form a C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹; alternatively R³ and R⁴ can together form ═O;and alternatively any of R and R², R and R³, R and R⁵, R⁴ and R¹¹, andR⁶ and R¹¹ can, together with the atoms linking them, form a 3-15membered heterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 43

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹; R³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; alternatively, R³ and R⁶ can,together with the atoms linking them, form a C₃₋₆cycloalkyl optionallysubstituted by 1-6 R¹⁹; and alternatively any of R¹ and R², R¹ and R³,R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹, and R⁶ and R¹¹ can, together with theatoms linking them, form a 3-15 membered heterocycloalkyl optionallysubstituted by 1-22 R¹⁹.

Embodiment 44

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹; R³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; alternatively, R³ and R⁶ can,together with the atoms linking them, form a C₃₋₆cycloalkyl optionallysubstituted by 1-6 R¹⁹; and alternatively any of R¹ and R², R¹ and R³,R¹ and R⁵, R⁴ and R¹¹, and R⁶ and R¹¹ can, together with the atomslinking them, form a 3-15 membered heterocycloalkyl optionallysubstituted by 1-22 R¹⁹.

Embodiment 45

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹; R³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; alternatively, R³ and R⁶ can,together with the atoms linking them, form a C₃₋₆cycloalkyl optionallysubstituted by 1-6 R¹⁹.

Embodiment 46

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R⁴, R⁵, and R⁶ are H; R² is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by 1-27R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; alternatively R³ and R⁶ can,together with the atoms linking them, form a C₃₋₆cycloalkyl optionallysubstituted by 1-6 R¹⁹; alternatively R³ and R⁴ can together form ═O;and alternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴and R¹¹, and R⁶ and R¹¹ can, together with the atoms linking them, forma 3-15 membered heterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 47

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R⁴, R⁵, and R⁶ are H; R² is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by 1-27R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; alternatively R³ and R⁶ can,together with the atoms linking them, form a C₃₋₆cycloalkyl optionallysubstituted by 1-6 R¹⁹; alternatively R³ and R⁴ can together form ═O;and alternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, R⁴ and R¹¹,and R⁶ and R¹¹ can, together with the atoms linking them, form a 3-15membered heterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 48

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R⁴, R⁵, and R⁶ are H; R³ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹;alternatively R³ and R⁶ can, together with the atoms linking them, forma C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹; and alternativelyany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶and R¹¹ can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 49

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R⁴, R⁵, and R⁶ are H; R³ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹;alternatively R³ and R⁶ can, together with the atoms linking them, forma C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹; and alternativelyany of R and R², R¹ and R³, R¹ and R⁵, R⁴ and R¹¹, and R⁶ and R¹¹ can,together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 50

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R⁴, R⁵, and R⁶ are H; R³ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹;alternatively R³ and R⁶ can, together with the atoms linking them, forma C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 51

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁ arylalkyl optionally substituted by 1-19 R¹⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₆₋₁₀-cycloalkylalkyl optionally substituted by1-10 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively R³ and R⁶ can, togetherwith the atoms linking them, form a C₃₋₆ cycloalkyl optionallysubstituted by 1-3 R¹⁹; alternatively R³ and R⁴ can together form ═O;and alternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹,and R⁴ and R¹¹ can, together with the atoms linking them, form a 3-15membered heterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 52

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁ arylalkyl optionally substituted by 1-19 R¹⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₆₋₁₀cycloalkylalkyl optionally substituted by1-10 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively R³ and R⁶ can, togetherwith the atoms linking them, form a C₃₋₆ cycloalkyl optionallysubstituted by 1-3 R¹⁹; alternatively R³ and R⁴ can together form ═O;and alternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, and R⁴ and R¹¹can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 53

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₂arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₆₋₁₀cycloalkylalkyl optionally substituted by1-10 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; alternatively R³ and R⁶ can, together with the atoms linkingthem, form a C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹; andalternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, and R⁴and R¹¹ can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 54

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₂arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₆₋₁₀cycloalkylalkyl optionally substituted by1-10 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; alternatively R³ and R⁶ can, together with the atoms linkingthem, form a C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹; andalternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, and R⁴ and R¹¹can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 55

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₂arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₆₋₁₀cycloalkylalkyl optionally substituted by1-10 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; alternatively R³ and R⁶ can, together with the atoms linkingthem, form a C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 56

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₂arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₆₋₁₀-cycloalkylalkyl optionally substituted by1-10 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively R³ and R⁶ can, togetherwith the atoms linking them, form a C₃₋₆ cycloalkyl optionallysubstituted by 1-3 R¹⁹; alternatively R³ and R⁴ can together form ═O;and alternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹,and R⁴ and R¹¹ can, together with the atoms linking them, form a 3-15membered heterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 57

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₂arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₆₋₁₀cycloalkylalkyl optionally substituted by1-10 R¹⁹, and 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively R³ and R⁶ can, togetherwith the atoms linking them, form a C₃₋₆ cycloalkyl optionallysubstituted by 1-3 R¹⁹; alternatively R³ and R⁴ can together form ═O;and alternatively any of R¹ and R², R¹ and R³, R¹ and R⁵, and R⁴ and R¹¹can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 58

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₆₋₁₀-cycloalkylalkyloptionally substituted by 1-10 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; R⁴, R⁵, and R⁶ are H; alternativelyR³ and R⁶ can, together with the atoms linking them, form aC₃₋₆cycloalkyl; and alternatively any of R¹ and R², R¹ and R³, R¹ andR⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together with the atoms linkingthem, form a 3-15 membered heterocycloalkyl optionally substituted by1-22 R¹⁹.

Embodiment 59

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₆₋₁₀-cycloalkylalkyloptionally substituted by 1-10 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; R⁴, R⁵, and R⁶ are H; alternativelyR³ and R⁶ can, together with the atoms linking them, form aC₃₋₆cycloalkyl; and alternatively any of R¹ and R², R¹ and R³, R¹ andR⁵, and R⁴ and R¹¹ can, together with the atoms linking them, form a3-15 membered heterocycloalkyl optionally substituted by 1-22 R¹⁹.

Embodiment 60

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₆₋₁₀-cycloalkylalkyloptionally substituted by 1-10 R¹⁹, and 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹; R⁴, R⁵, and R⁶ are H; alternativelyR³ and R⁶ can, together with the atoms linking them, form aC₃₋₆cycloalkyl.

Embodiment 61

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; alternatively R³ and R⁶ can, together with the atoms linking them,form a C₃₋₆cycloalkyl; and alternatively any of R¹ and R², R¹ and R³, R¹and R⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together with the atoms linkingthem, form a 3-7 membered heterocycloalkyl optionally substituted by1-11 R¹⁹.

Embodiment 62

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; alternatively R³ and R⁶ can, together with the atoms linking them,form a C₃₋₆cycloalkyl; and alternatively any of R¹ and R², R¹ and R³, R¹and R⁵, and R⁴ and R¹¹ can, together with the atoms linking them, form a3-7 membered heterocycloalkyl optionally substituted by 1-11 R¹⁹.

Embodiment 63

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; alternatively R³ and R⁶ can, together with the atoms linking them,form a C₃₋₆cycloalkyl.

Embodiment 64

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R³ and R⁶ can, together with the atomslinking them, form a C₃₋₆cycloalkyl; alternatively R³ and R⁴ cantogether form ═O; and alternatively any of R¹ and R², R¹ and R³, R¹ andR⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together with the atoms linkingthem, form a 3-7 membered heterocycloalkyl optionally substituted by1-11 R¹⁹.

Embodiment 65

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R³ and R⁶ can, together with the atomslinking them, form a C₃₋₆cycloalkyl; alternatively R³ and R⁴ cantogether form ═O; and alternatively any of R¹ and R², R¹ and R³, R¹ andR⁵, and R⁴ and R¹¹ can, together with the atoms linking them, form a 3-7membered heterocycloalkyl optionally substituted by 1-11 R¹⁹.

Embodiment 66

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R³ and R⁶ can, together with the atomslinking them, form a C₃₋₆cycloalkyl; alternatively R³ and R⁴ cantogether form ═O.

Embodiment 67

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; alternatively R³ and R⁶ can, together with the atoms linking them,form a cyclopropyl group optionally substituted by 1-3 R¹⁹; andalternatively any of R¹ and R³, R¹ and R⁵, R¹ and R¹¹, and R⁴ and R¹¹can, together with the atoms linking them, form a 3-7 memberedheterocycloalkyl optionally substituted by 1-11 R¹⁹.

Embodiment 68

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; alternatively R³ and R⁶ can, together with the atoms linking them,form a cyclopropyl group optionally substituted by 1-3 R¹⁹; andalternatively any of R¹ and R³, R¹ and R⁵, and R⁴ and R¹¹ can, togetherwith the atoms linking them, form a 3-7 membered heterocycloalkyloptionally substituted by 1-11 R¹⁹.

Embodiment 69

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; alternatively R³ and R⁶ can, together with the atoms linking them,form a cyclopropyl group optionally substituted by 1-3 R¹⁹.

Embodiment 70

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R³ and R⁶ can, together with the atomslinking them, form a cyclopropyl group; and alternatively any of R¹ andR³, R¹ and R⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together with the atomslinking them, form a 3-7 membered heterocycloalkyl optionallysubstituted by 1-11 R¹⁹.

Embodiment 71

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R³ and R⁶ can, together with the atomslinking them, form a cyclopropyl group; and alternatively any of R¹ andR³, R¹ and R⁵, and R⁴ and R¹¹ can, together with the atoms linking them,form a 3-7 membered heterocycloalkyl optionally substituted by 1-11 R¹⁹.

Embodiment 72

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-13R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R³ and R⁶ can, together with the atomslinking them, form a cyclopropyl group.

Embodiment 73

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-3 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,

C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, and 6-11 membered heteroarylalkyloptionally substituted by 1-7 R¹⁹; and alternatively any of R¹ and R²,R¹ and R³, R¹ and R⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together with theatoms linking them, form a 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 74

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-3 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,

C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, and 6-11 membered heteroarylalkyloptionally substituted by 1-7 R¹⁹; and alternatively any of R¹ and R²,R¹ and R³, R¹ and R⁵, and R⁴ and R¹¹ can, together with the atomslinking them, form a 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 75

The compound of any of Embodiments 1-19, wherein R¹, R⁴, R⁵, R⁶, and R¹¹are independently chosen from H and C₁₋₆alkyl optionally substituted by1-3 R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, and 6-10 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,

C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, and 6-11 membered heteroarylalkyloptionally substituted by 1-7 R¹⁹; and alternatively any of R¹ and R²,R¹ and R³, R¹ and R⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together with theatoms linking them, form a 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 76

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R¹⁹; R⁴,R⁵, and R⁶ are

H.

Embodiment 77

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are independently chosen from H and C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹,

C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, and 6-11 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹; and alternatively any of R¹ and R³,R¹ and R⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together withthe atoms linking them, form a 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 78

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are independently chosen from H and C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹,

C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, and 6-11 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹; and alternatively any of R¹ and R³,R¹ and R⁵, and R⁴ and R¹¹ can, together with the atoms linking them,form a 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 79

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are independently chosen from H and C₁₋₆alkyl optionally substitutedby 1-3 R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹,

C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, and 6-11 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹.

Embodiment 80

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; and alternatively any of R¹ and R³, R¹ and R⁵, R¹ andR¹¹, and R⁴ and R¹¹ can, together with the atoms linking them, form a5-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 81

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; and alternatively any of R¹ and R³, R¹ and R⁵, and R⁴and R¹¹ can, together with the atoms linking them, form a 5-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 82

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are

H.

Embodiment 83

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are

H; alternatively any of R¹ and R³, R¹ and R⁵, and R⁴ and R¹¹ can,together with the atoms linking them, form a 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹;

and alternatively R¹ and R¹¹ can, together with the atoms linking them,form a 5-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 84

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively any of R¹ and R³, R¹ and R⁵, and R⁴ andR¹¹ can, together with the atoms linking them, form a 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 85

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively any of R¹ and R³, and R⁴ and R¹¹ can,together with the atoms linking them, form a 5 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹; alternatively R¹ and R⁵ can, togetherwith the atoms linking them, form a 5-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹; and alternatively R¹ and R¹¹ can,together with the atoms linking them, form a 6-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 86

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively any of R¹ and R³, and R⁴ and R¹¹ can,together with the atoms linking them, form a 5 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹; alternatively R¹ and R⁵ can, togetherwith the atoms linking them, form a 5-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹.

Embodiment 87

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,and C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹; R³ is chosen fromH, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, and 6-11 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively any of R¹and R³, and R⁴ and R¹¹ can, together with the atoms linking them, form a5 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹;alternatively R¹ and R⁵ can, together with the atoms linking them, forma 5-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹; andalternatively R¹ and R¹¹ can, together with the atoms linking them, forma 6-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 88

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,and C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹; R³ is chosen fromH, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, and 6-11 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively any of R¹and R³, and R⁴ and R¹¹ can, together with the atoms linking them, form a5 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹;alternatively R¹ and R⁵ can, together with the atoms linking them, forma 5-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 89

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R² is H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₆₋₇cycloalkylalkyl optionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R¹ and R⁵ can, together with the atomslinking them, form a 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹; and alternatively R¹ and R¹¹ can, together withthe atoms linking them, form a 6-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 90

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R² is H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₆₋₇cycloalkylalkyl optionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R¹ and R⁵ can, together with the atomslinking them, form a 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 91

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R¹ and R⁵ can, together with the atomslinking them, form a 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹; and alternatively R¹ and R¹¹ can, together withthe atoms linking them, form a 6-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 92

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R¹ and R⁵ can, together with the atomslinking them, form a 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 93

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R¹ and R⁵ can, together with the atomslinking them, form a 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹; and alternatively R¹ and R¹¹ can, together withthe atoms linking them, form a 6-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 94

The compound of any of Embodiments 1-19, wherein R¹, R², and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹,

and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R¹⁹; R⁴,R⁵, and R⁶ are H; alternatively R¹ and R⁵ can, together with the atomslinking them, form a 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.

Embodiment 95

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,and C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹; R³ is chosen fromH, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, and 6-11 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively R¹ and R⁵can, together with the atoms linking them, form a 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹; and alternatively R¹and R¹¹ can, together with the atoms linking them, form a 6-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 96

The compound of any of Embodiments 1-19, wherein R¹ and R¹¹ areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,and C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹; R³ is chosen fromH, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, C₆₋₇cycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, and 6-11 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹; R⁴, R⁵, and R⁶ are H; alternatively R¹ and R⁵can, together with the atoms linking them, form a 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 97

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₆₋₇cycloalkylalkyl optionally substituted by 1-3 R¹⁹, and 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹; alternatively R¹ andR⁵ can, together with the atoms linking them, form a 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹; and alternatively R¹and R¹¹ can, together with the atoms linking them, form a 5-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 98

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₆₋₇cycloalkylalkyl optionally substituted by 1-3 R¹⁹, and 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹; alternatively R¹ andR⁵ can, together with the atoms linking them, form a 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 99

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₆₋₇cycloalkylalkyl optionally substituted by 1-3 R¹⁹, and 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹; alternatively R¹ andR⁵ can, together with the atoms linking them, form a 5 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹; and alternatively R¹and R¹¹ can, together with the atoms linking them, form a 6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 100

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₆₋₇cycloalkylalkyl optionally substituted by 1-3 R¹⁹, and 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹; alternatively R¹ andR⁵ can, together with the atoms linking them, form a 5 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 101

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, benzyl optionally substituted by 1-3 R¹⁹, C₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, and 6-7 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹; alternatively R¹ and R⁵ can, togetherwith the atoms linking them, form a pyrrolidinyl group optionallysubstituted by 1-3 R¹⁹; and alternatively R¹ and R¹¹ can, together withthe atoms linking them, form a piperidinyl group optionally substitutedby 1-3 R¹⁹.

Embodiment 102

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, benzyl optionally substituted by 1-3 R¹⁹, C₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, and 6-7 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹; alternatively R¹ and R⁵ can, togetherwith the atoms linking them, form a pyrrolidinyl group optionallysubstituted by 1-3 R¹⁹.

Embodiment 103

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, benzyl optionally substituted by 1-3 R¹⁹, C₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, and 6-7 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹; alternatively R¹ and R⁵ can, togetherwith the atoms linking them, form a pyrrolidinyl group; andalternatively R¹ and R¹¹ can, together with the atoms linking them, forma piperidinyl group.

Embodiment 104

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, benzyl optionally substituted by 1-3 R¹⁹, C₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, and 6-7 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹; alternatively R¹ and R⁵ can, togetherwith the atoms linking them, form a pyrrolidinyl group.

Embodiment 105

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is benzyl optionally substituted by 1-3 R¹⁹; alternativelyR¹ and R⁵ can, together with the atoms linking them, form a pyrrolidinylgroup; and alternatively R¹ and R¹¹ can, together with the atoms linkingthem, form a piperidinyl group.

Embodiment 106

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is benzyl optionally substituted by 1-3 R¹⁹; alternativelyR¹ and R⁵ can, together with the atoms linking them, form a pyrrolidinylgroup.

Embodiment 107

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is benzyl; alternatively R¹ and R⁵ can, together with theatoms linking them, form a pyrrolidinyl group; and alternatively R¹ andR¹¹ can, together with the atoms linking them, form a piperidinyl group.

Embodiment 108

The compound of any of Embodiments 1-19, wherein R¹, R², R⁴, R⁵, R⁶, andR¹¹ are H; R³ is benzyl; alternatively R¹ and R⁵ can, together with theatoms linking them, form a pyrrolidinyl group.

Embodiment 109

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³,—C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R)R¹)R²,—C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴R²²R²³,—N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)C(═O)R²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³,—NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —NR²⁴C(═O)R²⁸R²⁸, —NR²⁴P(═O)(22R²³)(NR²²R²³,—NR²⁴P(═)(OR²⁰)(OR²⁰), —NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —OP(═O)₂R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³,—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂R²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R²⁸R²⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰); alternatively, either orboth of R⁷ and R, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 110

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇-16arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰,and —S(═O)₂NR²²R²³; alternatively, either or both of R⁷

and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-15 R¹⁹.

Embodiment 111

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇-16arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 112

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-4R¹⁹, C₂₋₆alkenyl optionally substituted by 1-4 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-4 R¹⁹, C₆₋₁₀aryl optionally substituted by1-4 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-4 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-4 R¹⁹, C₄-8cycloalkylalkyloptionally substituted by 1-4 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-4 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-4 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-4 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-4 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)₂R²⁰,—OS(═O)₂R²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-4 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-4R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-4 R¹⁹ ora 5-6 membered heteroaryl optionally substituted by 1-4 R¹⁹.

Embodiment 113

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 114

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OS(═O)₂R²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰,and —S(═O)₂NR²²R²³; alternatively, either or both of R⁷

and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 115

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or both of R⁷and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 116

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl,C₆₋₁₀aryl, C₇₋₁₁arylalkyl, C₃₋₇cycloalkyl, C₄₋₈cycloalkylalkyl, 3-7membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-6membered heteroaryl, 6-21 membered heteroarylalkyl, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively,either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with theatoms linking them, form a C₆₋₁₀aryl, C₃₋₇cycloalkyl, 3-7 memberedheterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 117

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 118

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or both of R⁷and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 119

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or both of R⁷and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, or a 3-7membered heterocycloalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 120

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or bothof R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linkingthem, form a C₃₋₇cycloalkyl, or a 3-7 membered heterocycloalkyl.

Embodiment 121

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰; alternatively, either or bothof R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linkingthem, form a C₆₋₁₁-aryl optionally substituted by 1-11 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 122

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,and —OR²⁰; alternatively, either or both of R⁷ and R⁸, and/or R⁹ andR¹⁰, can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹.

Embodiment 123

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇-16arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 124

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ ischosen from H, C₁₋₆ alkyl optionally substituted by 1-13 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-9 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 125

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ and R⁹are independently chosen from C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆ alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 126

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ ischosen from C₁₋₆ alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ ischosen from C₁₋₆ alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aC₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹.

Embodiment 127

The compound of any of Embodiments 1-108, wherein R⁸ and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁷ and R¹⁰are independently chosen from C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁-aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 128

The compound of any of Embodiments 1-108, wherein R⁸ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 6-21 membered heteroarylalkyloptionally substituted by 1-27 R¹⁹ halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆ alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R andR¹⁰ are independently chosen from C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰ and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 129

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 130

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 131

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹ 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ and R⁹are independently chosen from C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁-cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 132

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ ischosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ ischosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R¹⁹ 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by 1-3R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰,and —OR²⁰; alternatively, either or both of R⁷ and R⁸, and/or R⁹ andR¹⁰, can, together with the atoms linking them, form a C₆₋₁₁-aryloptionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 133

The compound of any of Embodiments 1-108, wherein R⁸ and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁷ and R¹⁰are independently chosen from C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆-1aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 134

The compound of any of Embodiments 1-108, wherein R⁸ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₇-16arylalkyl optionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-3 R¹⁹ halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁷ and R¹⁰are independently chosen from C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 135

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁ arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 136

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 137

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀ cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 138

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 139

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ and R⁹are independently chosen from C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 140

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ ischosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₃₋₁₀ cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ ischosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀ cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 141

The compound of any of Embodiments 1-108, wherein R⁸ and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁷ and R¹⁰are independently chosen from C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀ cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 142

The compound of any of Embodiments 1-108, wherein R⁸ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀ cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁷ and R¹⁰ are independently chosenfrom C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆ alkynyl optionally substituted by 1-3 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aC₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 143

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aC₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀ cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 144

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl, 3-10membered heterocycloalkyl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 145

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 3-10membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or

R⁹ and R¹⁰, can, together with the atoms linking them, form a C₆₋₁₀aryl,C₃₋₁₀ cycloalkyl, 3-10 membered heterocycloalkyl or a 5-10 memberedheteroaryl.

Embodiment 146

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 3-10membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R ischosen from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl,halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and—OR²⁰; alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰,can, together with the atoms linking them, form a C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl or a 5-10 memberedheteroaryl.

Embodiment 147

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, 5-10membered heteroaryl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aC₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 3-10 membered heterocycloalkyl or a 5-10membered heteroaryl.

Embodiment 148

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, 5-10membered heteroaryl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, halogen,—CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 149

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₆ cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, eitheror both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a phenyl optionally substituted by 1-3 R¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 150

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₃₋₆ cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a phenyl optionallysubstituted by 1-3 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R¹⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 151

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ and R⁹ areindependently chosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3 R¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹ halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either

or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a phenyl optionally substituted by 1-3 R¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 152

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₃₋₆ cycloalkyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ ischosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, phenyl optionally substituted by 1-3 R¹⁹, C₃₋₆ cycloalkyloptionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷and R⁸, and/or R⁹ and R¹⁰, can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 153

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, eitheror both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 154

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyloptionally substituted by 1-3 R¹⁹, phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosen from H,C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, eitheror both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a phenyl, C₃₋₆ cycloalkyl, 3-6 memberedheterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 155

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ and R⁹ areindependently chosen from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, eitheror both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 156

The compound of any of Embodiments 1-108, wherein R⁷ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosen fromC₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl

optionally substituted by 1-3 R¹⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; R⁹ is chosen from C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, phenyl, C₃₋₆cycloalkyl,3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, eitheror both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a phenyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 157

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 memberedheteroaryl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aphenyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl or a 5-6 memberedheteroaryl.

Embodiment 158

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 memberedheteroaryl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosen from

H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aphenyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl or a 5-6 memberedheteroaryl.

Embodiment 159

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl, C₂₋₆alkynyl, phenyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and—OR²⁰; alternatively, either

or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a C₃₋₆cycloalkyl or a 3-6 membered heterocycloalkyl.

Embodiment 160

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkynyl, phenyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and—OR²⁰; R⁸ is chosen from H, C₁₋₆alkyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-6membered heterocycloalkyl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; alternatively, either

or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can, together with the atomslinking them, form a C₃₋₆cycloalkyl or a 3-6 membered heterocycloalkyl.

Embodiment 161

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁ cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, and —NR²²R²³; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aC₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁ cycloalkyloptionally substituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-15 R¹⁹.

Embodiment 162

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl keep tagging optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen,—CN, —C(═O)NR²²R²³, and —NR²²R²³; R⁸ is chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, and —NR²²R²³; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aC₆₋₁₁ aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-R¹⁹.

Embodiment 163

The compound of any of Embodiments 1-108, wherein R⁷ and R⁸ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, and —NR²²R²³; alternatively, R⁷ and R⁸ can, together withthe atoms linking them, form a C₆₋₁₁aryl optionally substituted by 1-11R¹⁹, or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 164

The compound of any of Embodiments 1-108, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-15 R¹⁹, halogen, —CN, —C(═O)NR²²R²³, and —NR²²R²³; R⁸ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, halogen,—CN, —C(═O)NR²²R²³, and —NR²²R²³; alternatively, R⁷ and R⁸ can, togetherwith the atoms linking them, form a C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, or a 5-15 membered heteroaryl optionally substituted by 1-15R¹⁹.

Embodiment 165

The compound of any of Embodiments 1-108, wherein R⁹ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, and —C(═O)NR²²R²³;alternatively, R⁹ and R¹⁰ can, together with the atoms linking them,form a C₃₋₁₁ cycloalkyl optionally substituted by 1-21 R¹⁹, or a 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹.

Embodiment 166

The compound of any of Embodiments 1-108, wherein R⁷, R⁸, R⁹, and R¹⁰are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁ cycloalkyl optionally substituted by 1-21 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹ halogen, —CN,—C(═O)NR²²R²³, and —NR²²R²³; alternatively, either or both of R⁷ and R⁸,and/or R⁹ and R¹⁰, can, together with the atoms linking them, form aC₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, a C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, a 5-15 membered heteroaryloptionally substituted by 1-15 R¹⁹, or a 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹.

Embodiment 167

The compound of any of Embodiments 1-108, wherein R⁷, R⁹, and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, and —NR²²R²³; R⁸ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-21 R¹⁹, halogen, —CN, —C(═O)NR²²R²³, and—NR²²R²³; alternatively, either or both of R⁷ and R⁸, and/or R⁹ and

R¹⁰, can, together with the atoms linking them, form a C₃₋₁₁-cycloalkyloptionally substituted by 1-21 R¹⁹, a C₆₋₁₁aryl optionally substitutedby 1-11 R¹⁹, a 5-15 membered heteroaryl optionally substituted by 1-15R¹⁹, or a 3-15 membered heterocycloalkyl optionally substituted by 1-28R¹⁹.

Embodiment 168

The compound of any of Embodiments 1-108, wherein R⁷ and R⁸ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, and —NR²²R²³; alternatively, R⁷ and R⁸ can, together withthe atoms linking them, form a C₆₋₁₁aryl optionally substituted by 1-11R¹⁹, or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 169

The compound of any of Embodiments 1-108, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-15 R¹⁹, halogen, —CN, —C(═O)NR²²R²³, and —NR²²R²³; R⁸ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, halogen,—CN, —C(═O)NR²²R²³, and —NR²²R²³; alternatively, R⁷ and R⁸ can, togetherwith the atoms linking them, form a C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, or a 5-15 membered heteroaryl optionally substituted by 1-15R¹⁹.

Embodiment 170

The compound of any of Embodiments 1-108, wherein R⁹ and R¹⁰ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, and —C(═O)NR²²R²³; alternatively, R⁹ and R¹⁰ can, together with theatoms linking them, form a C₃₋₁₁-cycloalkyl optionally substituted by1-21 R¹⁹, or a 3-15 membered heterocycloalkyl optionally substituted by1-28 R¹⁹.

Embodiment 171

The compound of any of Embodiments 1-108, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, and halogen; R⁸ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, and —NR²²R²³; alternatively, R⁷ and R⁸ can, together withthe atoms linking them, form a C₆₋₁₁aryl optionally substituted by 1-11R¹⁹, or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 172

The compound of any of Embodiments 1-108, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, and halogen; R⁸ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, halogen,—CN, —C(═O)NR²²R²³, and —NR²²R²³; alternatively, R⁷ and R⁸ can, togetherwith the atoms linking them, form a C₆₋₁₁-aryl optionally substituted by1-11 R¹⁹, or a 5-15 membered heteroaryl optionally substituted by 1-15R¹⁹.

Embodiment 173

The compound of any of Embodiments 1-108, wherein R⁹ is chosen from Hand C₁₋₆alkyl optionally substituted by 1-13 R¹⁹; R¹⁰ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, and —C(═O)NR²²R²³;alternatively, R⁹ and R¹⁰ can, together with the atoms linking them,form a C₃₋₁₁ cycloalkyl optionally substituted by 1-21 R¹⁹, or a 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹.

Embodiment 174

The compound of any of Embodiments 1-108, wherein R⁹ is C₁₋₆alkyloptionally substituted by 1-13 R¹⁹; R¹⁰ is chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R¹⁹, and —C(═O)NR²²R²³; alternatively, R⁹and R¹⁰ can, together with the atoms linking them, form aC₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, or a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹.

Embodiment 175

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted

by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, C₄-17cycloalkylalkyl optionally substituted by1-32 R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R¹⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰,—C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰,—C(═NNR²⁴C(═O)R²)R²⁰, —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂,—NR²²R²³, —NR²⁴R²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²³NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(22R²³)(NR²²R²³, —NR²⁴P(═)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NNR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—O(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³)OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,—S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —SP(═O)R²⁸R²⁸,—SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰), —SP(═O)(SR²⁰)(SR²⁰),—P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³), —P(═O)(OR²⁰)(OR²⁰), and—P(═O)(SR²⁰)(SR²⁰); alternatively, either or both of R¹² and R¹³, and/orR¹⁴ and R¹⁵, can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₃₋₁₁-cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹.

Embodiment 176

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted

by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹⁹, C₃₋₁₁-cycloalkyl optionallysubstituted by 1-21 R¹⁹, C₄-17cycloalkylalkyl optionally substituted by1-32 R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R¹⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —NR²⁴P(═O)R²⁸R²⁸,—NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²⁰), —OR²⁰, —OCN,—OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR², —SO₃R²⁷,—S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),and —P(═O)(OR²⁰)(OR²⁰); alternatively, either or both of R¹² and R¹³,and/or R¹⁴ and R¹⁵, can, together with the atoms linking them, form aC₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁-cycloalkyloptionally substituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-15 R¹⁹.

Embodiment 177

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇-16arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³),—NR²⁴P(═)(OR²⁰)(OR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,—OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²²³), —OP(═O)(OR²⁰)(OR²⁰), —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰);alternatively, either or both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 178

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇-16arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰,—SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R²⁸R²⁸,—P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); alternatively, eitheror both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 179

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇-16arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰,—SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R²⁸R²⁸,—P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); alternatively, eitheror both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atomslinking them, form a C₆₋₁₁-aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 180

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰,—S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R²⁸R²⁸,—P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); alternatively, eitheror both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the

atoms linking them, form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁ cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 181

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰);alternatively, either or both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 182

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, C₄17cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³; alternatively, either or both of R¹² and R¹³, and/or R¹⁴and R¹⁵, can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 183

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R², and —S(═O)₂NR²²R²³; alternatively, either or bothof R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linkingthem, form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 184

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³ alternatively, either or both of R¹²and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linking them,form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 185

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³ alternatively, either or both of R¹²and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linking them,form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-3 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 186

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 187

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 188

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or both of R¹²and R¹³ and/or R¹⁴ and R¹⁵, can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹ 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 189

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3

R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or bothof R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linkingthem, form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹ 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 190

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3

R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or bothof R¹² and R¹³ and/or R¹⁴ and R¹⁵, can, together with the atoms linkingthem, form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 191

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3

R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —R²⁴C(═O)R²⁰, —R²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 192

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3

R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —R²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 193

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —OR²⁰, and—S(═O)₂NR²²R²³.

Embodiment 194

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —NR²⁴C(═O)NR²²R²³.

Embodiment 195

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —OR²⁰, and—S(═O)₂NR²²R²³.

Embodiment 196

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —NR²⁴C(═O)NR²²R²³.

Embodiment 197

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —OR²⁰, and—S(═O)₂NR²²R²³.

Embodiment 198

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,and halogen.

Embodiment 199

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H and C₁₋₆alkyl optionally substituted by1-3 R¹⁹.

Embodiment 200

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl, halogen, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.

Embodiment 201

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl, halogen, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —NR²⁴C(═O)NR²²R²³.

Embodiment 202

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.

Embodiment 203

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, C₁₋₆alkyl, —NR²²R²³, —NR²⁴C(═O)R²⁰, and—NR²⁴C(═O)NR²²R²³.

Embodiment 204

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.

Embodiment 205

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, C₁₋₆alkyl, and halogen.

Embodiment 206

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H and C₁₋₆alkyl.

Embodiment 207

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted

by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹⁹, C₃₋₁₁-cycloalkyl optionallysubstituted by 1-21 R¹⁹, C₄-17cycloalkylalkyl optionally substituted by1-32 R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R¹⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰;alternatively, either or both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁ cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 208

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted

by 1-9 R¹⁹, C₆₋₁₁-aryl optionally substituted by 1-11 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-21 R¹⁹, C₄-17cycloalkylalkyl optionallysubstituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by1-27 R¹⁹, halogen, —CN, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰;alternatively, either or both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 209

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.

Embodiment 210

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are independently chosen from H, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, and—NR²⁴C(═O)NR²²R²³.

Embodiment 211

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.

Embodiment 212

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁵ areH; R¹⁴ is chosen from H, —NR²²R²³, —NR²⁴C(═O)R²⁰ and —NR²⁴C(═O)NR²²R²³.

Embodiment 213

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.

Embodiment 214

The compound of any of Embodiments 1-174, wherein R¹², R¹³, and R¹⁴ areH; R¹⁵ is chosen from H and halogen.

Embodiment 215

The compound of any of Embodiments 1-174, wherein R¹², R¹³, R¹⁴, and R¹⁵are H.

Embodiment 216

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆ alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄-17cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, and —OR²⁰; R¹⁶ andR¹⁸ are independently chosen from H, C₁₋₆alkyl

optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰,—C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰,—C(═NNR²⁴C(═O)R²¹)R²⁰, —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂,—NR²²R²³, —NR²⁴R²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)C(═O)R²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)NR²⁸R²⁸, —NR²⁴P(═O)(R²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²),—NR²⁴P(═)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R²⁸R²⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), or —P(═O)(SR²⁰)(SR²⁰); alternatively, R¹⁶ and R¹⁷can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 217

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl optionally substituted by 1-13 R¹⁹; R¹⁶ and R¹⁸ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³,—C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²)R)R²,—C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴C(═O)C(═O)R²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²),—NR²⁴P(═)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R²⁸R²⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), or —P(═O)(SR²⁰)(SR²⁰); alternatively, R¹⁶ and R¹⁷can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 218

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl optionally substituted by 1-3 R¹⁹; R¹⁶ and R¹⁸ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³,—C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²)R)R²,—C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴C(═O)C(═O)R²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²),—NR²⁴P(═)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R²⁸R²⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), or —P(═O)(SR²⁰)(SR²⁰); alternatively, R¹⁶ and R¹⁷can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 219

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰,—C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NR²²R²³)R²⁰,—C(═NNR²⁴C(═O)R²¹)R²⁰, —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂,—NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)C(═O)R²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²),—NR²⁴P(═)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R²⁸R²⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), or —P(═O)(SR²⁰)(SR²⁰); alternatively, R¹⁶ and R¹⁷can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 220

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-6 R¹⁹, C₇11arylalkyl optionally substitutedby 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —NC, —NO₂,—NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, R²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR², —SO₃R²⁷,—S(═O)₂NR²²R²³, and —S(═O)NR²²R²³; alternatively, R¹⁶ and R¹⁷ can,together with the atoms linking them, form a 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 221

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by1-1 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₇11arylalkyl optionally substitutedby 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —NC, —NO₂,—NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴R²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰,—SO₃R²⁷, —S(═O)₂NR²²R²³, and —S(═O)NR²²R²³; alternatively, R¹⁶ and R¹⁷can, together with the atoms linking them, form a 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 222

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂NR²²R²³,—SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³ and—S(═O)NR²²R²³; alternatively, R¹⁶ and R¹⁷ can, together with the atomslinking them, form a 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 223

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹ halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷,—S(═O)₂NR²²R²³, and —S(═O)NR²²R²³; alternatively, R¹⁶ and R¹⁷ can,together with the atoms linking them, form a 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 224

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹ halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively,R¹⁶ and R¹⁷ can, together with the atoms linking them, form a 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 225

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹ halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, R¹⁶ and R¹⁷ can,together with the atoms linking them, form a 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 226

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, R¹⁶ and R¹⁷ can, together with the atoms linking them,form a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹or a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 227

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl, C₇₋₁₁arylalkyl,C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, R¹⁶ and R¹⁷ can, together with the atoms linking them,form a 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 228

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₆₋₁₀aryl, C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, 3-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, R¹⁶ and R¹⁷ can,together with the atoms linking them, form a 3-10 memberedheterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 229

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, R¹⁶ and R¹⁷ can,together with the atoms linking them, form a 3-10 memberedheterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 230

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R², and —S(═O)₂NR²²R²³;alternatively, R¹⁶ and R¹⁷ can, together with the atoms linking them,form a 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 231

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 232

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 233

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from Hand C₁₋₆alkyl; R¹⁶ and R¹⁸ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, halogen, and —OR²⁰.

Embodiment 234

The compound of any of Embodiments 1-215, wherein R⁷ is H; R¹⁶ and R¹⁸are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, halogen, and —OR²⁰.

Embodiment 235

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, and halogen.

Embodiment 236

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H, C₁₋₆alkyl, and halogen.

Embodiment 237

The compound of any of Embodiments 1-215, wherein R¹⁶, R¹⁷, and R¹⁸ areindependently chosen from H and C₁₋₆alkyl.

Embodiment 238

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆ alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄-17cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, and —OR²⁰; R¹⁶ andR¹⁸ are independently chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰; alternatively, R¹⁶ and R¹⁷can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 239

The compound of any of Embodiments 1-215, wherein R¹⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄-17cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, and —OR²⁰; R¹⁶ andR¹⁸ are independently chosen from H, C₁₋₆alkyl

optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰; alternatively, R¹⁶ and R¹⁷can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 240

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H and C₁₋₆alkyl optionally substituted by1-3 R¹⁹.

Embodiment 241

The compound of any of Embodiments 1-215, wherein R⁷ is H; R¹⁶ and R¹⁸are independently chosen from H and C₁₋₆alkyl.

Embodiment 242

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H and C₁₋₄alkyl.

Embodiment 243

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H and C₁₋₃alkyl.

Embodiment 244

The compound of any of Embodiments 1-215, wherein R¹⁷ is H; R¹⁶ and R¹⁸are independently chosen from H and methyl.

Embodiment 245

The compound of any of Embodiments 1-215, wherein R¹⁶, R¹⁷, and R¹⁸ areH.

Embodiment 246

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-13R³⁹, C₂₋₆alkenyl optionally substituted by 1-11 R³⁹, C₂₋₆alkynyloptionally substituted by 1-9 R³⁹, C₆₋₁₁aryl optionally substituted by1-11 R³⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R³⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R³⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R³⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R³⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R³⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰,—C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰, —C(═NR³⁵)NR³²R³³,—C(═NOH)NR³²R³³, —C(═NOR³⁶)R³⁰, —C(═NNR³²R³³)R³⁰, —C(═NNR³⁴C(═O)R³¹)R³⁰,—C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂, —NR³²R³³,—NR³⁴NR³²R³³, —N═NR³⁴, ═NR³⁰, ═NOR³⁰, —NR³⁴R³⁶, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,—NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰, —NR³⁴C(═O)NR³⁴C(═O)OR³⁰,—NR³⁴C(═NR³⁵)NR³²R³³, —NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴C(═S)R³⁰,—NR³⁴C(═S)OR³⁰, —NR³⁴C(═S)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,—NR³⁴P(═O)R³⁸R³⁸, —NR³⁴P(═O)(NR³²R³³)(NR³²R³³), —NR³⁴P(═)(OR³⁰)(OR³⁰),—NR³⁴P(═O)(SR³⁰)(SR³⁰), —OR³⁰, ═O, —OCN, —OC(═O)R³⁰, —OC(═O)NR³²R³³,—OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³, —OS(═O)R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂R³⁰,—OS(═O)₂NR³²R³³, —OP(═O)R³⁸R³⁸, —OP(═O)(NR³²R³³)(NR³²R³³),—OP(═O)(OR³⁰)(OR³⁰), —OP(═O)(SR³⁰)(SR³⁰), —Si(R³⁴)₃, —SCN, ═S,—S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,—SP(═O)R³⁸R³⁸, —SP(═O)(NR³²R³³)(NR³²R³³), —SP(═O)(OR³⁰)(OR³⁰),—SP(═O)(SR³⁰)(SR³⁰), —P(═O)R³⁸R³⁸, —P(═O)(NR²²R²³)(NR³²R³³),—P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰).

Embodiment 247

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-6R³⁹, C₂₋₆alkenyl optionally substituted by 1-6 R³⁹, C₂₋₆alkynyloptionally substituted by 1-6 R³⁹, C₆₋₁₁aryl optionally substituted by1-6 R³⁹, C₇-16arylalkyl optionally substituted by 1-6 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R³⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R³⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R³⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R³⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R³⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰,—C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰, —C(═NR³⁵)NR³²R³³,—C(═NOH)NR³²R³³, —C(═NOR³⁶)R³⁰, —C(═NR³²R³³)R³⁰, —C(═NNR³⁴C(═O)R³¹)R³⁰,—C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂, —NR³²R³³,—NR³⁴NR³²R³³, —N═NR³⁴, ═NR³⁰, ═NOR³⁰, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,—NR³⁴C(═O)NR³²R³³, —R³⁴C(═O)NR³⁴C(═O)R³⁰, —NR³⁴C(═O)NR³⁴C(═O)OR³⁰,—NR³⁴C(═NR³⁵)NR³²R³³, —NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴C(═S)R³⁰,—NR³⁴C(═S)OR³⁰, —NR³⁴C(═S)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,—NR³⁴P(═O)R³⁸R³⁸, —NR³⁴P(═O)(NR³²R³³)(R³²R³³), —NR³⁴P(═O)(OR³⁰)(OR³⁰),—NR³⁴P(═O)(SR³⁰)(SR³⁰), —OR³⁰, ═O, —OCN, —OC(═O)R³⁰, —OC(═O)NR³²R³³,—OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³, —OS(═O)R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂R³⁰,—OS(═O)₂NR³²R³³, —OP(═O)R³⁸R³⁸, —OP(═O)(NR³²R³³)(R³²R³³),—OP(═O)(OR³⁰)(OR³⁰), —OP(═O)(SR³⁰)(SR³⁰), —Si(R³⁴)₃, —SCN, ═S,—S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,—SP(═O)R³⁸R³⁸, —SP(═O)(NR³²R³³)(NR³²R³³), —SP(═O)(OR³⁰)(OR³⁰),—SP(═O)(SR³⁰)(SR³⁰), —P(═O)R³⁸R³⁸, —P(═O)(NR³²R³³)(NR³²R³³),—P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰).

Embodiment 248

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-6R³⁹, C₂₋₆alkenyl optionally substituted by 1-6 R³⁹, C₂₋₆alkynyloptionally substituted by 1-6 R³⁹, C₆₋₁₁aryl optionally substituted by1-6 R³⁹, C₇-16arylalkyl optionally substituted by 1-6 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R³⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R³⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R³⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R³⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R³⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰,—C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —NC, —NO₂, —NR³²R³³, —NR³⁴NR³²R³³,—NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰, —NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹,—NR³⁴C(═O)C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰,—NR³⁴C(═O)NR³⁴C(═O)OR³⁰, —NR³⁴C(═NR³⁵)NR³²R³³, —NR³⁴C(═O)C(═O)NR³²R³³,—NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O, —OCN, —OC(═O)R³⁰,—OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³, —Si(R³⁴)₃, —SCN, ═S,—S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,—P(═O)R³⁸R³⁸, —P(═O)(NR³²³)(NR³²R³³), —P(═O)(OR³⁰)(OR³⁰), and—P(═O)(SR³⁰)(SR³⁰).

Embodiment 249

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyloptionally substituted by 1-3 R³⁹, C₆₋₁₁aryl optionally substituted by1-3 R³⁹, C₇-16arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R³⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R³⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R³⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R³⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰,—C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —NC, —NO₂, —NR³²R³³, —NR³⁴NR³²R³³,—NR³⁴⁰R³⁶, —NR³⁴C(═O)R³⁰, —NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹,—NR³⁴C(═O)C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰,—NR³⁴C(═O)NR³⁴C(═O)OR³⁰, —NR³⁴C(═NR³⁵)NR³²R³³, —NR³⁴C(═O)C(═O)NR³²R³³,—NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O, —OCN, —OC(═O)R³⁰,—OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³, —Si(R³⁴)₃, —SCN, ═S,—S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,—P(═O)R³⁸R³⁸, —P(═O)(NR³²³)(NR³²R³³), —P(═O)(OR³⁰)(OR³⁰), and—P(═O)(SR³⁰)(SR³⁰).

Embodiment 250

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —NC, —NO₂, —NR³²R³³,—NR³⁴NR³²R³³, —NR³⁴⁰R³⁶, —NR³⁴C(═O)R³⁰, —NR³⁴C(═O)C(═O)R³⁰,—NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³,—NR³⁴C(═O)NR³⁴C(═O)R³⁰, —NR³⁴C(═O)NR³⁴C(═O)OR³⁰, —NR³⁴C(═NR³⁵)NR³²R³³,—NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OCN, —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,—Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷,—S(═O)₂NR³²R³³, —S(═O)NR³²R³³, —P(═O)R³⁸R³⁸, —P(═O)(NR³²R³³)(NR³²R³³),—P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰).

Embodiment 251

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)OR³¹, —NR³⁴C(═O)NR³²R³²R³³, —NR³⁴S(═O)₂R³¹,—NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O, —OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃,═S, —S(═O)_(n)R³⁰, —S(═O)₂OR³, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,—P(═O)R³⁸R³⁸, —P(═O)(NR³²R³³)(NR³²R³³), —P(═O)(OR³⁰)(OR³⁰), and—P(═O)(SR³⁰)(SR³⁰).

Embodiment 252

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,—OR³⁰, ═O, —OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³,—S(═O)₂NR³²R³³, and —S(═O)NR³²R³³.

Embodiment 253

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.

Embodiment 254

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.

Embodiment 255

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₆₋₁₀aryl optionally substituted by 1-3 R³⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R³⁹ 3-6 membered heterocycloalkyl optionally substituted by 1-3R³⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R³⁹, halogen,—CN, —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³,—NR³⁴C(═O)R³⁰, —NR³⁴S(═O)₂R³¹, —OR³⁰, ═O, —OC(═O)R³⁰, —OC(═O)NR³²R³³,—Si(R³⁴)₃, —S(═O)_(n)R³⁰, and —S(═O)₂NR³²R³³.

Embodiment 256

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₆₋₁₀aryl optionally substituted by 1-3 R³⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R³⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3R³⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R³⁹, halogen,—CN, —C(═O)R³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, —NR³⁴S(═O)₂R³¹,—OR³⁰, ═O, —S(═O)_(n)R³⁰, and —S(═O)₂NR³²R³³.

Embodiment 257

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₆₋₁₀aryl optionally substituted by 1-3 R³⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R³⁹ 3-6 membered heterocycloalkyl optionally substituted by 1-3R³⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R³⁹, halogen,—CN, —C(═O)R³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, —OR³⁰, and ═O.

Embodiment 258

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)R³⁰, —C(═O)NR³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, —OR³⁰, and═O.

Embodiment 259

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, and —OR³⁰.

Embodiment 260

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-13R³⁹, C₂₋₆alkenyl optionally substituted by 1-11 R³⁹, C₂₋₆alkynyloptionally substituted by 1-9 R³⁹, C₆₋₁₁aryl optionally substituted by1-11 R³⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R³⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R³⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R³⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R³⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R³⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R³⁹, halogen, —CN, —C(═O)NR³²R³³, —NO₂, —NR³²R³³,and —OR³⁰.

Embodiment 261

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-13R³⁹.

Embodiment 262

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₆₋₁₀aryl optionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R³⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R³⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R³⁹, halogen, —C(═O)OR³⁰, —NR³²R³³, and —OR³⁰.

Embodiment 263

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, phenyl optionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R³⁹, 3-6 membered heterocycloalkyl optionallysubstituted by 1-3 R³⁹, 5-6 membered heteroaryl optionally substitutedby 1-3 R³⁹ halogen, —C(═O)OR³⁰, —NR³²R³³, and —OR³⁰.

Embodiment 264

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl, phenyl optionally substituted by1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl optionallysubstituted by 1-3 R³⁹, 5-6 membered heteroaryl, halogen, —C(═O)OR³⁰,—NR³²R³³, and —OR³⁰.

Embodiment 265

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl, phenyl optionally substituted by1 R³⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl optionallysubstituted by 1 R³⁹, 5-6 membered heteroaryl, halogen, —C(═O)OR³,—NR³²R³³, and —OR³⁰.

Embodiment 266

The compound of any of Embodiments 1-240, wherein R¹⁹ at each occurrenceis independently chosen from C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 3-6membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —C(═O)OR³⁰,—NR³²R³³, and —OR³⁰.

Embodiment 267

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁴⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁴⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁴⁹, C₆₋₁₁aryl optionally substituted by1-6 R⁴⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁴⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁴⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R⁴⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R⁴⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R⁴⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R⁴⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R⁴⁹.

Embodiment 268

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁴⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁴⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁴⁹, C₆₋₁₀aryl optionally substituted by1-6 R⁴⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R⁴⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁴⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R⁴⁹, and 5-10 memberedheteroaryl optionally substituted by 1-6 R⁴⁹.

Embodiment 269

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, C₂₋₆ alkenyl optionally substituted by 1-3 R⁴⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁴⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁴⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 270

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 271

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₇11arylalkyloptionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R⁴⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3R⁴⁹, and 5-6 membered heteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 272

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆ cycloalkyl optionally substituted by 1-3R⁴⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁴⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 273

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆ cycloalkyl, 3-6 membered heterocycloalkyl,and 5-6 membered heteroaryl.

Embodiment 274

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴,R³⁵, R³⁶ and R³⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 275

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴,R³⁵, R³⁶ and R³⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl.

Embodiment 276

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴,R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 277

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-6R⁴⁹.

Embodiment 278

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 279

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R⁴⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R⁴⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R⁴⁹.

Embodiment 280

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₆₋₁₁aryl optionally substituted by 1-3R⁴⁹, C₃₋₆ cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 281

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹ 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 282

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, phenyl optionally substituted by 1-3 R⁴⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 283

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl optionally substituted by1-3 R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.

Embodiment 284

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, phenyl optionally substituted by 1-3 R⁴⁹,C₃₋₆ cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.

Embodiment 285

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl optionally substituted by1-3 R⁴⁹ cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl.

Embodiment 286

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, phenyl optionally substituted by 1-3 R⁴⁹cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl.

Embodiment 287

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl optionally substituted by1 R⁴⁹, C₃₋₆ cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.

Embodiment 288

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, phenyl optionally substituted by 1 R⁴⁹,C₃₋₆ cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.

Embodiment 289

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 290

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, phenyl, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 291

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl.

Embodiment 292

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H, phenyl, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl.

Embodiment 293

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R⁴⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R⁴⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹,R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independently chosen from Hand C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 294

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₆₋₁₀aryl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 295

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹.

Embodiment 296

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 297

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1-3 R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶ andR³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹.

Embodiment 298

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 299

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1-3 R⁴⁹, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 300

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 301

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³, R³⁶ andR³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹.

Embodiment 302

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1 R⁴⁹,C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 303

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁴⁹.

Embodiment 304

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 305

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl, cyclopropyl, 5membered heterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁴⁹.

Embodiment 306

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 307

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R⁴⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R⁴⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹,R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independently chosen from Hand C₁₋₆alkyl.

Embodiment 308

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₆₋₁₀aryl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 309

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 310

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 311

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1-3 R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶ andR³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 312

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 313

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1-3 R⁴⁹, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 314

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 315

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 316

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1 R⁴⁹,C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 317

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 318

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 319

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl, cyclopropyl, 5membered heterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 320

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 321

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R⁴⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R⁴⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹,R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 322

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₆₋₁₀aryl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 323

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is H.

Embodiment 324

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 325

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1-3 R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is H.

Embodiment 326

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is H.

Embodiment 327

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1-3 R⁴⁹, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is H.

Embodiment 328

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁴⁹, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is H.

Embodiment 329

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl optionally substitutedby 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶ andR³⁷ at each occurrence is H.

Embodiment 330

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl optionally substituted by 1 R⁴⁹,C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is H.

Embodiment 331

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 332

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 333

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, phenyl, cyclopropyl, 5membered heterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 334

The compound of any of Embodiments 1-266, wherein R²⁰ at each occurrenceis independently chosen from H, phenyl, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 335

The compound of any of Embodiments 1-266, wherein R²⁰, R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 336

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-13 R⁴⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁴⁹, C₂₋₆alkynyloptionally substituted by 1-9 R⁴⁹, C₆₋₁₁aryl optionally substituted by1-11 R⁴⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁴⁹,C₃₋₁₁-cycloalkyl optionally substituted by 1-21 R⁴⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁴⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁴⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁴⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁴⁹.

Embodiment 337

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁴⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁴⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁴⁹, C₆₋₁₁aryl optionally substituted by1-3 R⁴⁹, C₇₋₁₁ arylalkyl optionally substituted by 1-3 R⁴⁹,C₃₋₁₁-cycloalkyl optionally substituted by 1-3 R⁴⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R⁴⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R⁴⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R⁴⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 338

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁴⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁴⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁴⁹, C₇₋₁₁ arylalkyl optionally substituted by 1-3 R⁴⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 339

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 340

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl, C₆₋₁₀aryl,C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, and5-10 membered heteroaryl.

Embodiment 341

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl, C₆₋₁₀aryl, andC₇₋₁₁arylalkyl.

Embodiment 342

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl, phenyl, and benzyl.

Embodiment 343

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl and C₆₋₁₀ aryl.

Embodiment 344

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is independently chosen from C₁₋₆alkyl and phenyl.

Embodiment 345

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 346

The compound of any of Embodiments 1-335, wherein R²⁸ and R³⁸ at eachoccurrence is C₁₋₆alkyl.

Embodiment 347

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁵⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁵⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁵⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁵⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁵⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁵⁹; alternatively, anyR²² and R²³ and/or R³² and R³³ may form, together with the nitrogen atomto which they are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R⁶⁹.

Embodiment 348

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁵⁹, C₆₋₁₁aryl optionallysubstituted by 1-3 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3R⁵⁹, C₃₋₁₁-cycloalkyl optionally substituted by 1-3 R⁵⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R⁵⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-3 R⁵⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R⁵⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R⁵⁹; alternatively, anyR²² and R²³ and/or R³² and R³³ may form, together with the nitrogen atomto which they are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁶⁹.

Embodiment 349

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; alternatively, any R²² andR²³ and/or R³² and R³³ may form, together with the nitrogen atom towhich they are attached, a 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁶⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁶⁹.

Embodiment 350

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 351

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁵⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁵⁹; alternatively, any R²² and R²³ and/orR³² and R³³ may form, together with the nitrogen atom to which they areattached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3R⁶⁹ or a 5-10 membered heteroaryl optionally substituted by 1-3 R⁶⁹.

Embodiment 352

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁵⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁵⁹.

Embodiment 353

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl, C₆₋₁₀aryl,C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, and5-10 membered heteroaryl; alternatively, any R²² and R²³ and/or R³² andR³³ may form, together with the nitrogen atom to which they areattached, a 3-10 membered heterocycloalkyl or a 5-10 memberedheteroaryl.

Embodiment 354

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl, C₆₋₁₀aryl,C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, and5-10 membered heteroaryl.

Embodiment 355

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, and5-10 membered heteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 356

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁵⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹.

Embodiment 357

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, phenyl optionallysubstituted by 1-3 R⁵⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹.

Embodiment 358

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, phenyl optionallysubstituted by 1-3 R⁵⁹, and 6 membered heteroaryl optionally substitutedby 1-3 R⁵⁹.

Embodiment 359

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H, phenyl optionallysubstituted by 1 R⁵⁹, and 6 membered heteroaryl optionally substitutedby 1 R⁵⁹.

Embodiment 360

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyloptionally substituted

by 1-9 R⁵⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁵⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R⁵⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R⁵⁹, C₄-17cycloalkylalkyl optionally substituted by1-32 R⁵⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R⁵⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R⁵⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R⁵⁹, and6-21 membered heteroarylalkyl optionally substituted by 1-27 R⁵⁹; R²³,R³² and R³³ at each occurrence is independently chosen from H andC₁₋₆alkyl; alternatively, any R²² and R²³ and/or R³² and R³³ may form,together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁶⁹ or a 5-15membered heteroaryl optionally substituted by 1-15 R⁶⁹.

Embodiment 361

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₁-aryl optionally substituted by1-3 R⁵⁹, C₇-16arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₁-cycloalkyl optionally substituted by 1-3 R⁵⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence isindependently chosen from H and C₁₋₆alkyl; alternatively, any R²² andR²³ and/or R³² and R³³ may form, together with the nitrogen atom towhich they are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁶⁹.

Embodiment 362

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl; alternatively,any R²² and R²³ and/or R³² and R³³ may form, together with the nitrogenatom to which they are attached, a 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁶⁹ or a 5-10 membered heteroaryloptionally substituted by 1-3 R⁶⁹.

Embodiment 363

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 364

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁵⁹ 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁵⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence isindependently chosen from H and C₁₋₆alkyl; alternatively, any R²² andR²³ and/or R³² and R³³ may form, together with the nitrogen atom towhich they are attached, a 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁶⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁶⁹.

Embodiment 365

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁵⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁵⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 366

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl,C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl; R²³, R³² and R³³ at each occurrence is independently chosenfrom H and C₁₋₆alkyl; alternatively, any R²² and R²³ and/or R³² and R³³may form, together with the nitrogen atom to which they are attached, a3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 367

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁ arylalkyl,C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl; R²³, R³² and R³³ at each occurrence is independently chosenfrom H and C₁₋₆alkyl.

Embodiment 368

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 369

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₆₋₁₀aryl optionally substituted by 1-3R⁵⁹, and 5-10 membered heteroaryl optionally substituted by 1-3 R⁵⁹;R²³, R³² and R³³ at each occurrence is independently chosen from H andC₁₋₆ alkyl.

Embodiment 370

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁵⁹, and 5-6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³,R³² and R³³ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 371

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁵⁹, and 6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³,R³² and R³³ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 372

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, phenyl optionally substituted by 1 R⁵⁹,and 6 membered heteroaryl optionally substituted by 1 R⁵⁹; R²³, R³² andR³³ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 373

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyloptionally substituted

by 1-9 R⁵⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁵⁹, C₇16arylalkyloptionally substituted by 1-19 R⁵⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R⁵⁹, C₄-17cycloalkylalkyl optionally substituted by1-32 R⁵⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R⁵⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R⁵⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R⁵⁹, and6-21 membered heteroarylalkyl optionally substituted by 1-27 R⁵⁹; R²³,R³² and R³³ at each occurrence is H; alternatively, any R²² and R²³and/or R³² and R³³ may form, together with the nitrogen atom to whichthey are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R⁶⁹.

Embodiment 374

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₁aryl optionally substituted by1-3 R⁵⁹, C₇-16arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R⁵⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H;alternatively,

any R²² and R²³ and/or R³² and R³³ may form, together with the nitrogenatom to which they are attached, a 3-15 membered heterocycloalkyloptionally substituted by 1-3 R⁶⁹ or a 5-15 membered heteroaryloptionally substituted by 1-3 R⁶⁹.

Embodiment 375

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at eachoccurrence is H; alternatively, any R²² and R²³ and/or R³² and R³³ mayform, together with the nitrogen atom to which they are attached, a 3-10membered heterocycloalkyl optionally substituted by 1-3 R⁶⁹ or a 5-10membered heteroaryl optionally substituted by 1-3 R⁶⁹.

Embodiment 376

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at eachoccurrence is H.

Embodiment 377

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, C₇11arylalkyloptionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁵⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁵⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H;alternatively, any R²² and R²³ and/or R³² and R³³ may form, togetherwith the nitrogen atom to which they are attached, a 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁶⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R⁶⁹.

Embodiment 378

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁵⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁵⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H.

Embodiment 379

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl,C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl; R²³, R³² and R³³ at each occurrence is H; alternatively, anyR²² and R²³ and/or R³² and R³³ may form, together with the nitrogen atomto which they are attached, a 3-10 membered heterocycloalkyl or a 5-10membered heteroaryl.

Embodiment 380

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl,C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl; R²³, R³² and R³³ at each occurrence is H.

Embodiment 381

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at eachoccurrence is H.

Embodiment 382

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, C₆₋₁₀aryl optionally substituted by 1-3R⁵⁹, and 5-10 membered heteroaryl optionally substituted by 1-3 R⁵⁹;R²³, R³² and R³³ at each occurrence is H.

Embodiment 383

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁵⁹, and 5-6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³,R³² and R³³ at each occurrence is H.

Embodiment 384

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, phenyl optionally substituted by 1-3R⁵⁹, and 6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³,R³² and R³³ at each occurrence is H.

Embodiment 385

The compound of any of Embodiments 1-346, wherein R²² at each occurrenceis independently chosen from H, phenyl optionally substituted by 1 R⁵⁹,and 6 membered heteroaryl optionally substituted by 1 R⁵⁹; R²³, R³² andR³³ at each occurrence is H.

Embodiment 386

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆ alkyl.

Embodiment 387

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is H.

Embodiment 388

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆ alkyloptionally substituted by 1-13 R⁵⁹; alternatively, any R²² and R²³and/or R³² and R³³ may form, together with the nitrogen atom to whichthey are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R⁶⁹.

Embodiment 389

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆ alkyloptionally substituted by 1-6 R⁵⁹; alternatively, any R²² and R²³ and/orR³² and R³³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by 1-6R⁶⁹ or a 5-15 membered heteroaryl optionally substituted by 1-6 R⁶⁹.

Embodiment 390

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆ alkyloptionally substituted by 1-6 R⁵⁹; alternatively, any R²² and R²³ and/orR³², and R³³ may form, together with the nitrogen atom to which they areattached, a 3-10 membered heterocycloalkyl optionally substituted by 1-6R⁶⁹ or a 5-10 membered heteroaryl optionally substituted by 1-6 R⁶⁹.

Embodiment 391

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆ alkyloptionally substituted by 1-6 R⁵⁹; alternatively, any R²² and R²³ and/orR³² and R³³ may form, together with the nitrogen atom to which they areattached, a 3-6 membered heterocycloalkyl optionally substituted by 1-6R⁶⁹ or a 5-6 membered heteroaryl optionally substituted by 1-6 R⁶⁹.

Embodiment 392

The compound of any of Embodiments 1-346, wherein R²², R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆ alkyloptionally; alternatively, any R²² and R²³ and/or R³² and R³³ may form,together with the nitrogen atom to which they are attached, a 3-6membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 393

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-13 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁷⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁷⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁷⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁷⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰,—C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³, —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰,—C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰, —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂,—NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═O)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰,—NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³, —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰,—NR⁷⁴C(═S)OR⁷⁰, —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —NR⁷⁴P(═)(OR⁷⁰)(OR⁷⁰),—NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, ═O, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³,—OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³, —OS(═O)R⁷⁰, —OS(═O)₂R⁷, —OS(═O)₂OR⁷⁰,—OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³ (NR⁷²R⁷³),—OP(═O)(OR⁷⁰)(OR⁷⁰), —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S,—S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),—SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰).

Embodiment 394

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁷⁹,C₂₋₆ alkynyl optionally substituted by 1-6 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁷⁹, C₃11cycloalkyl optionally substituted by 1-6 R⁷⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R⁷⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R⁷⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R⁷⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰,—C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³, —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰,—C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰, —C(═NNR⁷⁴C(═O)OR⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂,—NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)C(═O)R⁷⁰, —R⁷⁴C(═O)OR, —NR⁷⁴C(═O)C(═O)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰,—NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³, —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰,—NR⁷⁴C(═S)OR⁷⁰, —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³)—NR⁷⁴P(═)(OR⁷⁰)(OR⁷⁰),—NR⁷⁴P(═)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, ═O, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³,—OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³, —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰,—OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³,—OP(═O)(OR⁷⁰)(OR⁷⁰), —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S,—S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),—SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(R⁷²R⁷³72R⁷³),—P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰).

Embodiment 395

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁷⁹,C₂₋₆ alkynyl optionally substituted by 1-6 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —NC, —NO₂, —NR⁷²R⁷³,—NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴⁰R⁷⁶, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴C(═O)C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═O)OR,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰,—NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³, —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹,—NR⁷⁴S(═O)₂NR⁷²R⁷³, —NR⁷⁴P(═O)R⁷⁸R⁷⁸,—NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³)—NR⁷⁴P(═O)(OR⁷⁰)(OR⁷), —OR⁷⁰, ═O, —OCN,—OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³, —OS(═O)R⁷⁰,—OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸,—OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —OP(═O)(OR⁷⁰)(OR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S,—S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),—SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), and—P(═O)(OR⁷⁰)(OR⁷⁰).

Embodiment 396

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁷⁹,C₂₋₆ alkynyl optionally substituted by 1-6 R⁷⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹, 5-10 memberedheteroaryl optionally substituted by 1-6 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —NC, —NO₂, —NR⁷²R⁷³,—NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴R⁷⁶, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴C(═O)OR, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —NR⁷⁴P(═)(OR⁷⁰)(OR⁷⁰),—OR⁷⁰, ═O, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰,—OC(═NR⁷⁵)NR⁷²R⁷³, —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰,—OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³ (NR⁷²R⁷³),—OP(═O)(OR⁷⁰)(OR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S, —S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷,—SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³, —P(═O)R⁷⁸R⁷⁸,—P(═O)(NR⁷²R⁷³)(R⁷²R⁷³), and —P(═O)(OR⁷⁰)(OR⁷⁰).

Embodiment 397

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁷⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁷⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁷⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁷⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR¹, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹,—NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, ═O, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷²R⁷³,—OC(═O)OR⁷⁰, —OS(═O)₂NR⁷²R⁷³, —Si(R⁷⁴)₃, —SCN, —S(═O)R⁷⁰,—S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³2R, —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),and —P(═O)(OR⁷⁰)(OR⁷⁰).

Embodiment 398

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁷⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁷⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁷⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁷⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³, —NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴C(═O)OR, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—OR⁷⁰, ═O, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OS(═O)₂NR⁷²R⁷³, —S(═O)_(n)R⁷⁰,and —S(═O)₂NR⁷²R⁷³.

Embodiment 399

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁷⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁷⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁷⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁷⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷⁰, —OR⁷⁰, ═O, —S(═O)_(n)R⁷⁰ and—S(═O)₂NR⁷²R⁷³.

Embodiment 400

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁷⁹,C₇₋₁₁ arylalkyl optionally substituted by 1-3 R⁷⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁷⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁷⁹, 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰,—C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷²R⁷³,—NR⁷⁴S(═O)₂R⁷, —OR⁷⁰, ═O, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³.

Embodiment 401

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁷⁹,3-10 membered heterocycloalkyl optionally substituted by 1-3 R⁷⁹, 5-10membered heteroaryl optionally substituted by 1-3 R⁷⁹, —CN, and—C(═O)R⁷⁰.

Embodiment 402

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, 5-6membered heterocycloalkyl optionally substituted by 1-3 R⁷⁹, 5-9membered heteroaryl optionally substituted by 1-3 R⁷⁹, —CN, and—C(═O)R⁷⁰.

Embodiment 403

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1 R⁷⁹, phenyl, 6 membered heterocycloalkyl optionallysubstituted by 1 R⁷⁹, 5-9 membered heteroaryl optionally substituted by1-3 R⁷⁹, —CN, and —C(═O)R⁷⁰.

Embodiment 404

The compound of any of Embodiments 1-392, wherein R³⁹ at each occurrenceis independently chosen from C₁₋₆alkyl and 5-9 membered heteroaryloptionally substituted by 1-3 R⁷⁹; R⁵⁹ and R⁶⁹ at each occurrence isindependently C₁₋₆alkyl; R⁴⁹ at each occurrence is independently chosenfrom C₁₋₆ alkyl optionally substituted by 1 R⁷⁹, phenyl, 6 memberedheterocycloalkyl optionally substituted by 1 R⁷⁹, 5 membered heteroaryloptionally substituted by 1-3 R⁷⁹, —CN, and —C(═O)R⁷⁰.

Embodiment 405

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl, phenyl, 5-6membered heterocycloalkyl, 5-9 membered heteroaryl, —CN, and —C(═O)R⁷⁰.

Embodiment 406

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl, phenyl, 5-6membered heterocycloalkyl, and 5-9 membered heteroaryl.

Embodiment 407

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-13 R⁷⁹.

Embodiment 408

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹.

Embodiment 409

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹.

Embodiment 410

The compound of any of Embodiments 1-392, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹at each occurrence is independently C₁₋₆alkyl.

Embodiment 411

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R⁸⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R⁸⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁸⁹, C₆₋₁₁aryloptionally substituted by 1-11 R⁸⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R⁸⁹, C₃₋₁₁ cycloalkyl optionally substituted by 1-21R⁸⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁸⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁸⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R⁸⁹, 5-15membered heteroaryl optionally substituted by 1-15 R⁸⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R⁸⁹.

Embodiment 412

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R⁸⁹, C₂₋₆alkenyl optionally substituted by1-6 R⁸⁹, C₂₋₆alkynyl optionally substituted by 1-6 R⁸⁹, C₆₋₁₀aryloptionally substituted by 1-6 R⁸⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-6 R⁸⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁸⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R⁸⁹, and 5-10membered heteroaryl optionally substituted by 1-6 R⁸⁹.

Embodiment 413

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁸⁹, C₂₋₆alkenyl optionally substituted by1-3 R⁸⁹, C₂₋₆alkynyl optionally substituted by 1-3 R⁸⁹, C₆₋₁₀aryloptionally substituted by 1-3 R⁸⁹, C₇11arylalkyl optionally substitutedby 1-3 R⁸⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁸⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-10membered heteroaryl optionally substituted by 1-3 R⁸⁹.

Embodiment 414

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁸⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁸⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁸⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁸⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁸⁹.

Embodiment 415

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, 3-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 416

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁸⁹, phenyl optionally substituted by 1-3R⁸⁹, benzyl optionally substituted by 1-3 R⁸⁹, C₅₋₆cycloalkyl optionallysubstituted by 1-3 R⁸⁹, 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁸⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁸⁹.

Embodiment 417

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 418

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyloptionally substituted by 1-3 R⁸⁹, and 5-6 membered heteroaryl.

Embodiment 419

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyloptionally substituted by 1 R⁸⁹, and 5-6 membered heteroaryl.

Embodiment 420

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, and 5-6 membered heterocycloalkyl optionally substituted by1-3 R⁸⁹.

Embodiment 421

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, and 5-6 membered heterocycloalkyl optionally substituted byC₁₋₆alkyl.

Embodiment 422

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, and 5-6 membered heterocycloalkyl.

Embodiment 423

The compound of any of Embodiments 1-410, wherein R⁷⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, and 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹; R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶and R⁷⁷ at each occurrence is H.

Embodiment 424

The compound of any of Embodiments 1-410, wherein R⁷⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, and 5-6 memberedheterocycloalkyl optionally substituted by C₁₋₆alkyl; R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶and R⁷⁷ at each occurrence is H.

Embodiment 425

The compound of any of Embodiments 1-410, wherein R⁷⁰ at each occurrenceis independently chosen from H, C₁₋₆alkyl, and 5-6 memberedheterocycloalkyl; R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is H.

Embodiment 426

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl.

Embodiment 427

The compound of any of Embodiments 1-410, wherein R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵,R⁷⁶ and R⁷⁷ at each occurrence is H.

Embodiment 428

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R⁹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁹⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁹⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁹⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁹⁹; alternatively, anyR⁷² and R⁷³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by1-28 R¹⁰⁹ or a 5-15 membered heteroaryl optionally substituted by 1-15R¹⁰⁹.

Embodiment 429

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R⁹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁹⁹,C₂₋₆ alkynyl optionally substituted by 1-6 R⁹⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R⁹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R⁹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R⁹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R⁹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R⁹⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R⁹⁹; alternatively, anyR⁷² and R⁷³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by 1-6R¹⁰⁹ or a 5-15 membered heteroaryl optionally substituted by 1-6 R¹⁰⁹.

Embodiment 430

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁹⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁹⁹, C₆11aryl optionallysubstituted by 1-3 R⁹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3R⁹⁹, C₃11cycloalkyl optionally substituted by 1-3 R⁹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R⁹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R⁹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-3 R⁹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R⁹⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R⁹⁹; alternatively, anyR⁷² and R⁷³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by 1-3R¹⁰⁹ or a 5-15 membered heteroaryl optionally substituted by 1-3 R¹⁰⁹.

Embodiment 431

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁹⁹,C₂₋₆ alkynyl optionally substituted by 1-3 R⁹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁹⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁹⁹; alternatively, any R⁷² andR⁷³ may form, together with the nitrogen atom to which they areattached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3R¹⁰⁹ or a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁰⁹.

Embodiment 432

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁹⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁹⁹; alternatively, any R⁷² and R⁷³ mayform, together with the nitrogen atom to which they are attached, a 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁰⁹ or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁰⁹.

Embodiment 433

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3 R⁹⁹, benzyloptionally substituted by 1-3 R⁹⁹, C₅₋₆cycloalkyl optionally substitutedby 1-3 R⁹⁹, 5-6 membered heterocycloalkyl optionally substituted by 1-3R⁹⁹, and 5-6 membered heteroaryl optionally substituted by 1-3 R⁹⁹;alternatively, any R⁷² and R⁷³ may form, together with the nitrogen atomto which they are attached, a 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁰⁹ or a 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁰⁹.

Embodiment 434

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3 R⁹⁹, benzyloptionally substituted by 1-3 R⁹⁹, C₅₋₆cycloalkyl optionally substitutedby 1-3 R⁹⁹, 5-6 membered heterocycloalkyl optionally substituted by 1-3R⁹⁹, and 5-6 membered heteroaryl optionally substituted by 1-3 R⁹⁹.

Embodiment 435

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl, phenyl, benzyl,C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; alternatively, any R⁷² and R⁷³ may form, together with thenitrogen atom to which they are attached, a 5-6 memberedheterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 436

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl, phenyl, benzyl,C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.

Embodiment 437

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3 R⁹⁹, andbenzyl optionally substituted by 1-3 R⁹⁹.

Embodiment 438

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁹⁹.

Embodiment 439

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl, phenyl, andbenzyl.

Embodiment 440

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 441

The compound of any of Embodiments 1-427, wherein R⁷² and R⁷³ at eachoccurrence is H.

Embodiment 442

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-13R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁸⁹, C₂₋₆alkynyloptionally substituted by 1-9 R⁸⁹, C₆₋₁₁aryl optionally substituted by1-11 R⁸⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁸⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁸⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R⁸⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R⁸⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R⁸⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R⁸⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R⁸⁹.

Embodiment 443

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁸⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁸⁹, C₆₋₁₁aryl optionally substituted by1-3 R⁸⁹, C₇-16arylalkyl optionally substituted by 1-3 R⁸⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R⁸⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R⁸⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R⁸⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R⁸⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁸⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R⁸⁹.

Embodiment 444

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁸⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁸⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁸⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁸⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁸⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁸⁹.

Embodiment 445

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R⁸⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁸⁹, C₇11arylalkyloptionally substituted by 1-3 R⁸⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁸⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁸⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁸⁹.

Embodiment 446

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R⁸⁹, phenyl optionally substituted by 1-3 R⁸⁹, benzyl optionallysubstituted by 1-3 R⁸⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R⁸⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁸⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁸⁹.

Embodiment 447

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl, phenyl, benzyl, C₃₋₆ cycloalkyl,3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 448

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl optionally substituted by 1-3R⁸⁹, phenyl optionally substituted by 1-3 R⁸⁹, and benzyl optionallysubstituted by 1-3 R⁸⁹.

Embodiment 449

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis independently chosen from C₁₋₆alkyl, phenyl, and benzyl.

Embodiment 450

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis C₁₋₆alkyl optionally substituted by 1-3 R⁸⁹.

Embodiment 451

The compound of any of Embodiments 1-441, wherein R⁷⁸ at each occurrenceis C₁₋₆alkyl.

Embodiment 452

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-13 halogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁-aryl, C₇₋₁₁arylalkyl, C₃₋₁₁cycloalkyl, C₄₋₁₇cycloalkylalkyl, 3-15 memberedheterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 memberedheteroaryl, 6-21 membered heteroarylalkyl, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —C(═O)C(═O)R¹¹⁰, —C(═NR¹¹⁰)R¹¹⁰,—C(═NR¹¹⁰⁾NR¹¹⁰R¹¹⁰, —C(═NOH)NR¹¹⁰R¹¹⁰, —C(═NOR¹¹⁰)R¹¹⁰,—C(═NNR¹¹⁰R¹¹⁰)R¹¹⁰, —C(═NNR¹¹⁰C(═O)R¹¹⁰)R¹¹⁰,—C(═NNR¹¹⁰C(═O)OR¹¹⁰)R¹¹⁰, —C(═S)NR¹¹⁰R¹¹⁰, —NC, —NO₂, —NR¹¹⁰R¹¹⁰,—NR¹¹⁰NR¹¹⁰R¹¹⁰, —N═NR¹¹⁰, ═NR¹¹⁰, ═NOR¹¹⁰, —NR¹¹⁰R¹¹⁰, —NR¹¹⁰C(═O)R¹¹⁰,—NR¹¹⁰C(═O)C(═O)R, —NR¹¹⁰C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)C(═O)OR¹¹⁰,—NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰C(═O)R¹¹⁰,—NR¹¹⁰C(═O)NR¹¹⁰C(═O)OR¹¹⁰, —NR¹¹⁰C(═NR¹¹⁰)NR¹¹⁰R¹¹⁰,—NR¹¹⁰C(═O)C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰C(═S)R¹¹⁰, —NR¹¹⁰C(═S)OR¹¹⁰,—NR¹¹⁰C(═S)NR¹¹⁰R¹¹⁰, —NR¹¹⁰S(═O)₂R¹¹⁰, —NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰,—NR¹¹⁰P(═O)R¹¹¹R¹¹¹, —NR¹¹⁰P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰),—NR¹¹⁰P(═O)(OR¹¹⁰)(OR¹¹⁰), —NR¹¹⁰P(═O)(SR¹¹⁰)(SR), —OR¹¹⁰, =, —OCN,—OC(═O)R¹¹⁰, —OC(═O)NR¹¹⁰R¹¹⁰, —OC(═O)OR¹¹⁰, —OC(═NR¹¹⁰)NR¹¹⁰R¹¹⁰,—OS(═O)R¹¹⁰, —OS(═O)₂R¹¹⁰, —OS(═O)₂OR¹¹⁰, —OS(═O)₂NR¹¹⁰R¹¹⁰,—OP(═O)R¹¹¹R¹¹¹, —OP(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —OP(═O)(OR¹¹⁰)(OR¹¹⁰),—OP(═O)(SR¹¹⁰)(SR¹¹⁰), —Si(R¹¹⁰)₃, —SCN, ═S, —S(═O)_(n)R¹¹⁰,—S(═O)₂OR¹¹⁰, —SO₃R¹¹⁰, —S(═O)₂NR¹¹⁰OR¹¹⁰, —S(═O)NR¹¹⁰R¹¹⁰,—SP(═O)R¹¹¹R¹¹¹, —SP(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —SP(═O)(OR¹¹⁰)(OR¹¹⁰),—SP(═O)(SR¹¹⁰)(SR¹¹⁰), —P(═O)R¹¹¹R¹¹¹, —P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰),—P(═O)(OR¹¹⁰)(OR¹¹⁰), and —P(═O)(SR¹¹⁰)(SR¹¹⁰).

Embodiment 453

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 halogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁aryl,C₇₋₁₆arylalkyl, C₃₋₁₁cycloalkyl, C₄₋₁₇cycloalkylalkyl, 3-15 memberedheterocycloalkyl, 4-15 membered heterocycloalkylalkyl, 5-15 memberedheteroaryl, 6-15 membered heteroarylalkyl, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —C(═O)C(═O)R¹¹⁰, —NC, —NO₂, —NR¹¹⁰R¹¹⁰,—NR¹¹⁰NR¹¹⁰, —NR¹¹⁰OR¹¹⁰, —NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)C(═O)R¹¹⁰,—NR¹¹⁰C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰,—NR¹¹⁰C(═O)NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰C(═O)OR¹¹⁰,—NR¹¹⁰C(═O)C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰S(═O)₂R¹¹⁰, —NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰,—NR¹¹⁰P(═O)R¹¹¹R¹¹¹, —NR¹¹⁰P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰),—NR¹¹⁰P(═O)(OR¹¹⁰)(OR¹¹⁰), —OR¹¹⁰, ═O, —OCN, —OC(═O)R¹⁰,—OC(═O)NR¹¹⁰R¹¹⁰, —OC(═O)OR¹¹⁰, —OS(═O)R¹¹⁰, —OS(═O)₂R¹¹⁰,—OS(═O)₂OR¹¹⁰, —OS(═O)₂NR¹¹⁰R¹¹⁰, —OP(═O)R¹¹¹R¹¹¹,—OP(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —OP(═O)(OR¹¹⁰)(OR¹¹⁰), —Si(R¹¹⁰)₃, —SCN,═S, —S(═O)_(n)R¹¹⁰, —S(═O)₂OR¹¹⁰, —SO₃R¹¹⁰, —S(═O)₂NR¹¹⁰R¹¹⁰,—S(═O)NR¹¹⁰R¹¹⁰, —P(═O)R¹¹¹R¹¹¹, —P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), and—P(═O)(OR¹¹⁰)(OR¹¹⁰).

Embodiment 454

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 halogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₇cycloalkylalkyl, 3-10 memberedheterocycloalkyl, 4-10 membered heterocycloalkylalkyl, 5-10 memberedheteroaryl, 6-10 membered heteroarylalkyl, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —NC, —NO₂, —NR¹¹⁰R¹¹⁰, —NR¹¹⁰OR¹¹⁰,—NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰,—NR¹¹⁰C(═O)NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰S(═O)₂R¹¹⁰, —NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰,—NR¹¹⁰P(═O)R¹¹¹R¹¹¹, —NR¹¹⁰P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰),—NR¹¹⁰P(═O)(OR¹¹⁰)(OR¹¹⁰), —OR¹¹⁰, ═O, —OCN, —OC(═O)R¹¹⁰,—OC(═O)NR¹¹⁰R¹¹⁰, —OS(═O)₂NR¹¹⁰R¹¹⁰, —OP(═O)R¹¹¹R¹¹¹,—OP(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —SCN, ═S, —S(═O)_(n)R¹¹⁰,—S(═O)₂NR¹¹⁰R¹¹⁰, —S(═O)NR¹¹⁰R¹¹⁰, —P(═O)R¹¹¹R¹¹¹, and—P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰).

Embodiment 455

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 halogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, 3-10 membered heterocycloalkyl, 5-10membered heteroaryl, halogen, —CN, —C(═O)R¹¹⁰, —C(═O)OR¹¹⁰,—C(═O)NR¹¹⁰R¹¹⁰, —NO₂, —NR¹¹⁰R¹¹⁰, —NR¹¹⁰R¹¹⁰, —NR¹¹⁰C(═O)R¹¹⁰,—NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰S(═O)₂R¹¹⁰, —NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰, —OR¹¹⁰,═O, —OCN, —OC(═O)R¹¹⁰, —S(═O)_(n)R¹¹⁰, —S(═O)₂NR¹¹⁰R¹¹⁰, and—S(═O)NR¹¹⁰R¹¹⁰.

Embodiment 456

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 halogen, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, benzyl,C₃₋₆ cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)R¹¹⁰, —C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —NO₂,—NR¹¹⁰R¹¹⁰, —NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰S(═O)₂R¹¹⁰,—NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰, —OR¹¹⁰, ═O, —S(═O)_(n)R¹¹⁰, and —S(═O)₂NR¹¹⁰R¹¹⁰.

Embodiment 457

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 halogen, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, benzyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)R¹¹⁰, —C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰R¹¹⁰,—NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰S(═O)₂R¹¹⁰, —OR¹¹⁰, ═O, —S(═O)_(n)R¹¹⁰, and—S(═O)₂NR¹¹⁰R¹¹⁰.

Embodiment 458

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 halogen, phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰R¹¹⁰, —OR¹¹⁰, ═O, —S(═O)_(n)R¹¹⁰,and —S(═O)₂NR¹¹⁰R¹¹⁰.

Embodiment 459

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 halogen, halogen, and —NR¹¹⁰R¹¹⁰.

Embodiment 460

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl, halogen, and—NR¹¹¹R¹¹⁰.

Embodiment 461

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is independently chosen from C₁₋₆alkyl and—NR¹¹⁰R¹¹⁰.

Embodiment 462

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is —NR¹¹⁰R¹¹⁰.

Embodiment 463

The compound of any of Embodiments 1-451, wherein R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is C₁₋₆alkyl.

Embodiment 464

The compound of any of Embodiments 1-451, wherein R⁷⁹ at each occurrenceis independently chosen from C₁₋₆alkyl and —NR¹¹⁰R¹¹⁰; R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is C₁₋₆alkyl.

Embodiment 465

The compound of any of Embodiments 1-451, wherein R⁷⁹ at each occurrenceis independently chosen from C₁₋₆alkyl and —NR¹¹⁰R¹¹⁰; R⁸⁹, R⁹⁹ and R¹⁰⁹at each occurrence is —NR¹¹⁰R¹¹⁰.

Embodiment 466

The compound of any of Embodiments 1-451, wherein R⁷⁹ at each occurrenceis —NR¹¹⁰R¹¹⁰; R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is C₁₋₆alkyl.

Embodiment 467

The compound of any of Embodiments 1-466, wherein R¹¹⁰ at eachoccurrence is independently chosen from H, C₁₋₆alkyl and C₁₋₆-haloalkyl.

Embodiment 468

The compound of any of Embodiments 1-466, wherein R¹¹⁰ at eachoccurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 469

The compound of any of Embodiments 1-466, wherein R¹¹⁰ at eachoccurrence is C₁₋₆alkyl.

Embodiment 470

The compound of any of Embodiments 1-466, wherein R¹¹⁰ at eachoccurrence is H.

Embodiment 471

The compound of any of Embodiments 1-470, wherein R¹¹⁰ at eachoccurrence is independently chosen from C₁₋₆alkyl and C₁₋₆-haloalkyl.

Embodiment 472

The compound of any of Embodiments 1-470, wherein R¹¹⁰ at eachoccurrence is C₁₋₆alkyl.

Embodiment 473

The compound of any of Embodiments 1-470, wherein R¹¹¹ at eachoccurrence is C₁₋₆-haloalkyl.

Embodiment 474

The compound of any of Embodiments 1-473, wherein n at each occurrenceis independently chosen from 0, 1, and 2.

Embodiment 475

The compound of any of Embodiments 1-473, wherein n at each occurrenceis independently chosen from 0 and 2.

Embodiment 476

The compound of any of Embodiments 1-473, wherein n at each occurrenceis independently chosen from 1 and 2.

Embodiment 477

The compound of any of Embodiments 1-473, wherein n at each occurrenceis independently chosen from 0 and 1.

Embodiment 478

The compound of any of Embodiments 1-473, wherein n at each occurrenceis 0.

Embodiment 479

The compound of any of Embodiments 1-473, wherein n at each occurrenceis 1.

Embodiment 480

The compound of any of Embodiments 1-473, wherein n at each occurrenceis 2.

Embodiment 481

The compound of any of Embodiments 1-480, wherein neither R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,R¹⁹,

R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, nor R²⁸ contain either of thefollowing chemical moieties

wherein W is O or S, and Z is N or C.

Embodiment 482

The compound of any of Embodiments 1-481, wherein neither R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,R¹⁹,

R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, nor R²⁸ is.

(a)

where W is O or S; J is O, NH or NCH₃; and R₃₀₁ is hydrogen or alkyl;

(b)

where W is O or S; Y₂ is absent, N, or CH; Z is N or CH; R₃₀₂ and R₃₀₄are independently hydrogen, hydroxyl, or an aliphatic group; providedthat if R₃₀₂ and R₃₀₄ are both present, one of R₃₀₂ or R₃₀₄

-   -   must be hydroxyl and if Y₂ is absent, R₃₀₄ must be hydroxyl; and    -   R₃₀₃ is hydrogen or aliphatic group;

where W is O or S; Y₁ and Z₁ are independently N, C or CH; or

where Z is N or CH; Y₂ is absent, N, or CH; W is O or S; R₂₁₁ and R₂₁₂are independently selected from hydrogen

-   -   or aliphatic group; R₂₀₁, R₂₀₂ and R₂₀₃ are independently        selected from hydrogen, hydroxyl, amino, halogen, alkoxy,        alkylamino, dialkylamino,    -   CF₃, CN, NO₂, sulfonyl, acyl, aliphatic group, substituted        aliphatic group, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, heterocyclic, and substituted heterocyclic;    -   wherein for the purpose of this Embodiment, the following        definitions apply:        -   an aliphatic group is a non-aromatic moiety that may be            saturated (e.g. single bond) or contain one or more units of            unsaturation, e.g., double and/or triple bonds; an aliphatic            group may be straight chained, branched or cyclic, contain            carbon, hydrogen or, optionally, one or more heteroatoms and            may be substituted or unsubstituted;        -   “acyl” refers to hydrogen, alkyl, partially saturated or            fully saturated cycloalkyl, partially saturated or fully            saturated heterocycle, aryl, and heteroaryl substituted            carbonyl groups;        -   “alkoxy” embraces linear or branched oxy-containing radicals            each having alkyl portions of one to about twenty carbon            atoms or, preferably, one to about twelve carbon atoms; and        -   “heterocyclic” refers to saturated, partially unsaturated            and unsaturated heteroatom-containing ringshaped radicals,            where the heteroatoms may be selected from nitrogen, sulfur            and oxygen;

Embodiment 483

The compound of any of Embodiments 1-482, wherein A is not S.

Embodiment 484

The compound of any of Embodiments 1-483, wherein R¹ is not —OR²⁰.

Embodiment 485

The compound of any of Embodiments 1-484, wherein R⁸ is nottetrahydrofuranyl substituted by 4 or 5 R¹⁹.

Embodiment 486

The compound of any of Embodiments 1-484, wherein R⁸ is not

wherein T¹ is R³⁹; T², T³, and T⁵ are independently chosen from R³⁰,—C(═O)R³⁰, —C(═O)NR³²R³³, —C(═O)OR³⁰, —C(═NR³⁵)NR³²R³³, —S(═O)R³⁰,—S(═O)₂R³⁰, —S(═O)₂OR³⁰, —S(═O)₂NR³²R³³, —P(═O)R³⁸R³⁸,—P(═O)(NR³²R³³)(NR³²R³³), —P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰);and T⁴ is R¹⁹.

Embodiment 487

The compound of any of Embodiments 1-484, wherein R⁸ is not

wherein T¹ is hydrogen, fluoro, azido, amino, hydroxyl, C₁₋₃alkoxy,mercapto, or C₁₋₃alkylthio; T², T³, and T⁵ are independently chosen fromR³⁰, —C(═O)R³⁰, —C(═O)NR³³, —C(═O)OR³⁰, —C(═NR³⁵)NR³²R³³, —S(═O)R³⁰,—S(═O)₂R³⁰, —S(═O)₂OR³⁰, —S(═O)₂NR³²R³³, —P(═O)R³R³,—P(═O)(NR³²R³³)(NR³²R³³), —P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰);and T⁴ is hydrogen, azido, methyl, hydroxymethyl, or fluoromethyl.

Embodiment 488

The compound of any of Embodiments 1-487, wherein R¹⁰ is not —CN.

Embodiment 489

The compound of any of Embodiments 1-488, wherein none of R¹ and R², R¹and R³, R¹ and R⁵, or R¹ and R¹¹, together with the atoms linking them,form a heterocycloalkyl optionally substituted by one or more R¹⁹ or aheteroaryl optionally substituted by one ore more R¹⁹.

Embodiment 490

The compound of any of Embodiments 1-488, wherein R¹ and R¹¹ do not,together with the atoms linking them, form a heterocycloalkyl optionallysubstituted by one or more R¹⁹ or a heteroaryl optionally substituted byone or more R¹⁹.

Embodiment 491

The compound of any of Embodiments 1-490, wherein neither R⁷ nor R¹⁰ isH, or neither R⁸ nor R⁹ is H.

Embodiment 492

The compound of Embodiment 491, wherein neither R⁷ nor R¹⁰ is H.

Embodiment 493

The compound of Embodiment 491, wherein neither R⁸ nor R⁹ is H.

Embodiment 494

The compound of any of Embodiments 1-493, wherein neither R³ and R⁴ norR⁵ and R⁶ together form ═O, ═NR²⁰, ═NOR²⁰, or ═S.

Embodiment 495

The compound of any of Embodiments 1-494, wherein neither R³ and R⁴ norR⁵ and R⁶ together form ═O.

Embodiment 496

The compound of any of Embodiments 1-495, wherein

-   -   (a) when R¹ is H, R² is neither aryl optionally substituted by        one or more R¹⁹ nor heteroaryl optionally substituted by one or        more R¹⁹,    -   (b) when R² is H, R¹ is neither optionally substituted by one or        more R¹⁹ nor heteroaryl optionally substituted by one or more        R¹⁹,    -   (c) R³, R⁴, R⁵, and R⁶ are not —NHR²², NHR²³, —SO₂NHR²²,        —SO₂NHR²³, —C(═O)NHR²², or —C(═O)NHR²³, wherein R²² and R²³ are        either aryl optionally substituted by one or more R⁵⁹ or        heteroaryl optionally substituted by one or more R⁵⁹, and    -   (d) R³, R⁴, R⁵, and R⁶ do not contain a group of formula —NHR,        —SO₂NHR, or —C(═O)NHR, wherein R is optionally substituted aryl,        or optionally substituted heteroaryl.

Embodiment 497

The compound of any of Embodiments 1-496, wherein the group of formula

does not together form a group of formula

wherein

-   -   B is an optionally substituted aryl, or optionally substituted        heteroaryl;    -   Q is a C₁₋₄alkylidene chain in which each methylene unit of said        Q is substituted by R² and R^(2′), and up to two non-adjacent        methylene units of said Q are optionally and independently        replaced by —SO₂ or —C(═O);    -   each R² is independently selected from H, —OH, C₁₋₁₀alkyl, C₁₋₁₀        aliphatic, (C₁₋₁₀ aliphatic)-NH—(C₁₋₁₀ aliphatic); —O—(C₁₋₁₀        aliphatic); —NH₂, —NH(C₁₋₁₀aliphatic), —N(C₁₋₁₀ aliphatic)₂,        —C(═O)R, aryl, or heteroaryl, wherein said aliphatic, aryl, or        heteroaryl is optionally substituted;    -   each R^(2′) is independently selected from H and an optionally        substituted C₁₋₁₀ aliphatic group; and    -   R is selected from an optionally substituted group selected from        C₁₋₁₀ aliphatic, aryl, aralkyl, heteroaryl, and heteroaralkyl;    -   wherein for the purpose of this Embodiment, the following        definitions apply:        -   “alkylidene chain” refers to a straight or branched carbon            chain that may be fully saturated or have one or more units            of un saturation and has two points of attachment to the            rest of the molecule;        -   “aliphatic” or “aliphatic group” means a straight-chain or            branched, substituted or unsubstituted C₁-C₈ hydrocarbon            chain that is completely saturated or that contains one or            more units of unsaturation, or a monocyclic C₃-C₅            hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is            completely saturated or that contains one or more units of            unsaturation, but which is not aromatic, that has a single            point of attachment to the rest of the molecule wherein any            individual ring in said bicyclic ring system has 3-7            members.

Embodiment 498

The compound of any of Embodiments 1-497, wherein R⁸ is neither aryloptionally substituted by one or more R¹⁹ nor heteroaryl optionallysubstituted by one or more R¹⁹.

Embodiment 499

The compound of any of Embodiments 1-498, wherein:

-   -   (a) when R⁹ is —NH₂, R¹⁰ is not —C(═O)NH₂;    -   (b) when R⁹ is —NHC(═S)NHCOPh, R¹⁰ is not —C(═O)OR²⁰, wherein        R²⁰ is alkyl optionally substituted by R⁴⁹; and    -   (c) R⁹ and R¹⁰ do not, together with the atoms linking them,        form a group of formula

wherein R¹⁹ is as defined herein.

Embodiment 500

The compound of any of Embodiments 1-499, wherein:

-   -   (a) when R⁹ is —NH₂, R¹⁰ is not —C(═O)NH₂; and    -   (b) R⁹ and R¹⁰ do not, together with the atoms linking them,        form a group of formula

or wherein R¹⁹ is as defined herein.

Embodiment 501

The compound of any of Embodiments 1-500, wherein R⁹ and R¹⁰ do not,together with the atoms linking them, form a group of formula

wherein R¹⁹ is as defined herein.

Embodiment 502

The compound of any of Embodiments 1-501, wherein neither R¹ and R² norR¹ and R³, together with the atoms linking them, form a heterocycloalkyloptionally substituted by one or more R¹⁹ or a heteroaryl optionallysubstituted by one or more R¹⁹, wherein R¹⁹ is as defined herein.

Embodiment 503

The compound of any of Embodiments 1-502, wherein R¹⁰ is not —CN, aryloptionally substituted by one or more R¹⁹, heterocycloalkyl optionallysubstituted by one or more R¹⁹, or heteroaryl optionally substituted byone or more R¹⁹, wherein R¹⁹ is as defined herein.

Embodiment 504

The compound of any of Embodiments 1-503, wherein R⁹ is neither —NH₂ nor—OH when R¹⁰ is —C(═O)R²⁰, —C(═O)OR²⁰, or —C(═O)NR²²R²³, wherein R²⁰,R²², and R²³ are as defined herein.

Embodiment 505

The compound of any of Embodiments 1-504, wherein when

(a) R⁹ is chosen from H, C₁-C₆alkyl, C₃-C₇cycloalkyl and—(CH₂)_(n1)—R⁴¹¹ wherein the subscript n1 is an integer of from 0 to 3and R⁴¹¹ is selected from C₁-C₆alkoxy, C₁-C₆alkylthio, mono- ordi-(C₁-C₆alkyl)amino, amino, phenyl, pyridyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl,pyrazolyl, and thienyl, wherein each of the rings is optionallysubstituted with from 1 to 3 substituents selected from halogen, N₃,NO₂, CN, C₁-C₆alkyl, OR⁴¹², N(R⁴¹²)₂, CO₂R⁴¹² and CON(R⁴¹²)₂, whereineach R⁴¹² is independently H or C₁-C₆alkyl; and

(b) R¹⁰ is chosen from —R⁴⁰¹, —OR⁴⁰¹, —SR⁴⁰¹, —N(R⁴¹⁰)R⁴⁰¹, —C(═O)R⁴⁰¹and —CH(OH)R⁴⁰¹, wherein R⁴¹⁰ is selected from H, C₁-C₆alkyl andC(═O)C₁-C₆alkyl; and R⁴⁰¹ is chosen from H, halo, CN, NO₂, —N₃,C₁-C₆alkyl, C₃-C₇cycloalkyl, —C(R⁴¹³)═C(R⁴¹³)₂, —C≡CR⁴¹³ or—(CH₂)_(n2)—R⁴¹⁴; wherein each R⁴¹³ is independently selected from H, F,Cl, Br, CN, C₁-C₆alkyl, C₃-C₇cycloalkyl, (CH₂)_(n2)—R⁴¹⁴ andC(O)—(CH₂)_(n2)—R⁴¹⁴; and wherein each subscript n2 is independently aninteger of from 0 to 3 and each R⁴¹⁴ is independently selected fromC₁-C₆alkoxy, C₁-C₆alkylthio, mono- or di-(C₁-C₆)alkylamino, amino,phenyl, pyridyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein eachof the rings is optionally substituted with from 1 to 3 substituentsselected from halogen, NO₂, —N₃, CN, (C₁-C₆)alkyl, OR⁴¹⁵, N(R⁴¹⁵)₂,CO₂R⁴¹⁵ and CON(R⁴¹⁵)₂, wherein each R⁴¹⁵ is independently H orC₁-C₆alkyl; and wherein any alkyl or cycloalkyl portions of R⁴⁰¹ areoptionally substituted with from one to five F substituents;

R¹ and R¹¹ do not, together with the atoms linking them, form a 6-7membered heterocycloalkyl optionally substituted by one or more R¹⁹,wherein R¹⁹ is as defined herein.

Embodiment 506

The compound of any of Embodiments 1-504, wherein when

(a) R⁹ is chosen from H, C₁-C₆alkyl, C₃-C₇cycloalkyl and—(CH₂)_(n1)—R⁴¹¹ wherein the subscript n1 is an integer of from 0 to 3and R⁴¹¹ is selected from C₁-C₆alkoxy, C₁-C₆alkylthio, mono- ordi-(C₁-C₆alkyl)amino, amino, phenyl, pyridyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl,pyrazolyl, and thienyl, wherein each of the rings is optionallysubstituted with from 1 to 3 substituents selected from halogen, N₃,NO₂, CN, C₁-C₆alkyl, OR⁴¹², N(R⁴¹²)₂, CO₂R⁴¹² and CON(R⁴¹²)₂, whereineach R⁴¹² is independently H or C₁-C₆alkyl; and

(b) R¹⁰ is chosen from —R⁴⁰¹, —OR⁴⁰¹, —SR⁴⁰¹, —N(R⁴¹⁰)R⁴⁰¹, —C(═O)R⁴⁰¹and —CH(OH)R⁴⁰¹, wherein R⁴¹⁰ is selected from H, C₁-C₆alkyl andC(═O)C₁-C₆alkyl; and R⁴⁰¹ is chosen from H, halo, CN, NO₂, —N₃,C₁-C₆alkyl, C₃-C₇cycloalkyl, —C(R⁴¹³)═C(R⁴¹³)₂, —C≡CR⁴¹³ or—(CH₂)_(n2)—R⁴¹⁴; wherein each R⁴¹³ is independently selected from H, F,Cl, Br, CN, C₁-C₆alkyl, C₃-C₇cycloalkyl, (CH₂)_(n2)—R⁴¹⁴ andC(O)—(CH₂)_(n2)—R⁴¹⁴; and wherein each subscript n2 is independently aninteger of from 0 to 3 and each R⁴¹⁴ is independently selected fromC₁-C₆alkoxy, C₁-C₆alkylthio, mono- or di-(C₁-C₆)alkylamino, amino,phenyl, pyridyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein eachof the rings is optionally substituted with from 1 to 3 substituentsselected from halogen, NO₂, —N₃, CN, (C₁-C₆)alkyl, OR⁴¹⁵, N(R⁴¹⁵)₂,CO₂R⁴¹⁵ and CON(R⁴¹⁵)₂, wherein each R⁴¹⁵ is independently H orC₁-C₆alkyl; and wherein any alkyl or cycloalkyl portions of R⁴⁰¹ areoptionally substituted with from one to five F substituents;

R¹ and R¹¹ do not, together with the atoms linking them, form a 6-7membered heterocycloalkyl optionally substituted by 1-4 R⁴⁰³, whereineach R⁴⁰³ is independently chosen from C₁-C₆alkyl, C₃-C₇cycloalkyl,—(CH₂)_(n4)—R⁴¹⁹ and —C(O)—(CH₂)_(n4)—R⁴¹⁹; wherein the subscript n4 isan integer of from 0 to 4 and each R⁴¹⁹ is independently selected fromC₁-C₆alkoxy, C₁-C₆alkylthio, mono- or di-(C₁-C₆)alkylamino, amino,phenyl, pyridyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein eachof the rings is optionally substituted with from 1 to 3 substituentsselected from halogen, N₃, NO₂, CN, C₁-C₆alkyl, —OR⁴²⁰, —N(R⁴²⁰)₂,CO₂R⁴²⁰ and CON(R⁴²⁰)₂, wherein each R⁴²⁰ is independently H orC₁-C₆alkyl; and wherein any alkyl or cycloalkyl portions of R⁴⁰³ areoptionally substituted with from one to five F substituents.

Embodiment 507

The compound of any of Embodiments 1-504, wherein R¹ and R¹¹ do not,together with the atoms linking them, form a 6-7 memberedheterocycloalkyl optionally substituted by 1-4 R⁴⁰³, wherein each R⁴⁰³is independently chosen from C₁-C₆alkyl, C₃-C₇cycloalkyl,—(CH₂)_(n4)—R⁴¹⁹ and —C(O)—(CH₂)_(n4)—R⁴¹⁹; wherein the subscript n4 isan integer of from 0 to 4 and each R⁴¹⁹ is independently selected fromC₁-C₆alkoxy, C₁-C₆alkylthio, mono- or di-(C₁-C₆)alkylamino, amino,phenyl, pyridyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein eachof the rings is optionally substituted with from 1 to 3 substituentsselected from halogen, N₃, NO₂, CN, C₁-C₆alkyl, —OR⁴²⁰, —N(R⁴²⁰)₂,CO₂R⁴²⁰ and CON(R⁴²⁰)₂, wherein each R⁴²⁰ is independently H orC₁-C₆alkyl; and wherein any alkyl or cycloalkyl portions of R⁴⁰³ areoptionally substituted with from one to five F substituents.

Embodiment 508

The compound of any of Embodiments 1-504, wherein R¹ and R¹¹ do not,together with the atoms linking them, form a 6-7 memberedheterocycloalkyl optionally substituted by one or more R¹⁹, wherein R¹⁹is as defined herein.

The above Embodiments include salts of acidic and basic compounds offormula (I). Preferably, the salts are pharmaceutically acceptable.Pharmaceutically acceptable acid addition salts of basic compounds offormula (I) include, but are not limited to, salts derived frominorganic acids such as hydrochloric, nitric, phosphoric, sulfuric,hydrobromic, hydriodic, and phosphorus, as well as the salts derivedfrom organic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Suchsalts thus include, but are not limited to, sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,caprylate, isobutyrate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate,and methanesulfonate. See, for example, Berge et al., “PharmaceuticalSalts,” J. of Pharmaceutical Science, 1977; 66:1-19.

Acid addition salts may be prepared by contacting a compound of formula(I) with a sufficient amount of the desired acid to produce the salt inthe conventional manner. The free base form of the compound of formula(I) may be regenerated by contacting the salt form with a base andisolating the free base in the conventional manner.

Pharmaceutically acceptable base salts of acidic compounds of formula(I) are formed with metals or amines, such as alkali and alkaline earthmetal hydroxides, or of organic amines. Examples of metals used ascations include, but are not limited to, sodium, potassium, magnesium,and calcium. Examples of suitable amines include, but are not limitedto, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine,and procaine. See, for example, Berge et al., “Pharmaceutical Salts,” J.of Pharmaceutical Science, 1977; 66:1-19.

Base salts may be prepared by contacting a compound of formula (I) witha sufficient amount of the desired base to produce the salt in theconventional manner. The acid form of the compound of formula (I) may beregenerated by contacting the salt form with an acid and isolating theacid in a conventional manner.

Some compounds of the present invention may exist as stereoisomers,including enantiomers, diastereomers, and geometric isomers. Geometricisomers include compounds of the present invention that have alkenylgroups, which may exist as entgegen or zusammen conformations, in whichcase all geometric forms thereof, both entgegen and zusammen, cis andtrans, and mixtures thereof, are within the scope of the presentinvention. Some compounds of the present invention have cycloalkylgroups, which may be substituted at more than one carbon atom, in whichcase all geometric forms thereof, both cis and trans, and mixturesthereof, are within the scope of the present invention. All of theseforms, including (R), (S), epimers, diastereomers, cis, trans, syn,anti, (E), (Z), tautomers, and mixtures thereof, are included in thecompounds of the present invention.

The compounds of the present invention may be in any physical form,including amorphous or crystalline solids in any polymorphic form, inany state of purity. Crystalline polymorphic forms include unsolvatedforms as well as solvated forms, such as hydrated forms.

III. Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising a compound of any of the above Embodiments (e.g., a compoundof formula (I) or a pharmaceutically acceptable salt thereof), togetherwith a pharmaceutically acceptable excipient therefor. For preparing apharmaceutical composition from a compound of the present invention,pharmaceutically acceptable excipients can be either solid or liquid. Anexcipient can be one or more substances which may act as, e.g., acarrier, diluent, flavoring agent, binder, preservative, tabletdisintegrating agent, or an encapsulating material. The pharmaceuticalcomposition may contain two or more compounds of the present invention(e.g., two different salt forms of a compound of formula (I), may beused together in the same pharmaceutical composition). Preferably, thepharmaceutical composition contains a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable salt formthereof. In one embodiment, the composition contains an amount of acompound of formula (I) or a pharmaceutically acceptable salt formthereof effective to treat an atypical protein kinase C (aPKC)-dependentdisorder or condition. Preferably, a compound of the present inventionwill cause a decrease in symptoms or disease indicia associated with anaPKC-dependent disorder as measured quantitatively or qualitatively. Thecomposition may also contain, in addition to a compound of formula (I)or a pharmaceutically acceptable salt form thereof and apharmaceutically acceptable excipient, another therapeutic compound,such as a compound useful in the treatment of cancer.

A compound of the present invention can be formulated as apharmaceutical composition in any delivery form, such as a syrup, anelixir, a suspension, a powder, a granule, a tablet, a capsule, alozenge, a troche, an aqueous solution, a cream, an ointment, a lotion,a gel, an emulsion, etc. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. Preferably, the pharmaceutical composition is a tablet orcapsule. In one embodiment, the pharmaceutical composition is a tablet.In another embodiment, the pharmaceutical composition is a capsule.

In powders, the excipient may be a finely divided solid in a mixturewith a finely divided active component (i.e., compound of the presentinvention). In tablets, the active component may be mixed with anexcipient having the necessary binding properties in suitableproportions and compacted in the shape and size desired. Suitableexcipients include magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, low melting wax, cocoa butter, and thelike.

The pharmaceutical composition preferably contains from 1% to 95% (w/w)of the active compound (i.e., compound of the present invention). Morepreferably, the pharmaceutical composition contains from 5% to 70% (w/w)of the active compound.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, may be melted and the activecomponent dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture may then be poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions.Formulations suitable for parenteral administration, such as, forexample, by intravenous, intramuscular, intradermal, and subcutaneousroutes, include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and nonaqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. In the practice of this invention,compositions can be administered, for example, by intravenous infusion,orally, topically, intraperitoneally, intravesically or intrathecally.The formulations of compounds can be presented in unit-dose ormulti-dose sealed containers, such as ampoules and vials. Injectionsolutions and suspensions can be prepared from sterile powders,granules, and tablets of the kind previously described.

A compound of the present invention, alone or in combination with othersuitable components, can be made into aerosol formulations (e.g., theycan be “nebulized”) to be administered via inhalation. Aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like.

Pharmaceutically acceptable excipients are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there is a widevariety of suitable formulations of pharmaceutical compositions of thepresent invention (see, e.g., Remington: The Science and Practice ofPharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams andWilkins, 2000).

The quantity of active component in a pharmaceutical composition may bevaried or adjusted from, e.g., 1 mg to 1,000 mg, 5 mg to 500 mg, 10 mgto 300 mg, or 25 mg to 250 mg, according to the particular applicationand the desired size of the dosage form.

The dose administered to a subject is preferably sufficient to induce abeneficial therapeutic response in the subject over time. The beneficialdose can vary from subject to subject depending upon, e.g., thesubject's condition, body weight, surface area, and side effectsusceptibility. Administration can be accomplished via single or divideddoses.

IV. Method of Treatment

In another aspect, the present invention provides a method of treatingan aPKC-dependent disorder or condition in a subject comprising:administering to the subject a compound of formula (I) as defined in anyof the above Embodiments or a pharmaceutically acceptable salt formthereof. In another aspect, the present invention provides a compound offormula (I) as defined in any of the above Embodiments or apharmaceutically acceptable salt form thereof for use in treating anaPKC-dependent disorder or condition in a subject. In another aspect,the present invention provides a compound of formula (I) as defined inany of the above Embodiments or a pharmaceutically acceptable salt formthereof for use in the preparation of a medicament for treating anaPKC-dependent disorder or condition in a subject. Preferably, thecompound is administered to the subject as a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient. Preferably, thecompound is administered to the subject in a pharmaceutically acceptableamount. In one embodiment, the aPKC-dependent condition or disorder iscancer. In another embodiment, the aPKC-dependent condition is selectedfrom non-small cell lung cancer (NSCLC), squamous cell carcinoma (e.g.,oesophageal squamous cell carcinoma), leukaemia, prostate cancer,non-Hodgkin's lymphoma (e.g., follicular lymphoma), endometrial cancer,lung cancer and breast cancer.

The aPKC-dependent disorder or condition can be treatedprophylactically, acutely, or chronically using compounds of the presentinvention, depending on the nature of the disorder or condition.Typically, the subject in each of these methods is human, although othermammals can also benefit from the administration of a compound of thepresent invention.

In another embodiment, the present invention provides a method oftreating a proliferative disorder in a subject, comprising administeringto the subject a compound of formula (I) as defined in any of the aboveEmbodiments or a pharmaceutically acceptable salt form thereof. Inanother aspect, the present invention provides a compound of formula (I)as defined in any of the above Embodiments or a pharmaceuticallyacceptable salt form thereof for use in treating a proliferativedisorder in a subject. In another aspect, the present invention providesa compound of formula (I) as defined in any of the above Embodiments ora pharmaceutically acceptable salt form thereof for use in thepreparation of a medicament for treating a proliferative disorder in asubject. Preferably, the compound is administered to the subject in apharmaceutical composition comprising a pharmaceutically acceptableexcipient. Preferably, the compound is administered to the subject in apharmaceutically acceptable amount. In certain embodiments, theproliferative disorder is aPKC-dependent. In certain embodiments, theproliferative disorder is cancer. In certain embodiments, theproliferative disorder is selected from non-small cell lung cancer(NSCLC), squamous cell carcinoma (e.g., oesophageal squamous cellcarcinoma), leukaemia, prostate cancer, non-Hodgkin's lymphoma (e.g.,follicular lymphoma), endometrial cancer, lung cancer and breast cancer.

The proliferative disorder can be treated prophylactically, acutely, orchronically using a compound of the present invention, depending on thenature of the disorder or condition. Typically, the subject in each ofthese methods is human, although other mammals can also benefit from theadministration of a compound of the present invention.

In therapeutic applications, the compounds of the present invention canbe prepared and administered in a wide variety of oral and parenteraldosage forms. Thus, the compounds of the present invention can beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the compounds described herein can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. In another embodiment, thecompounds of the present invention are delivered orally. The compoundscan also be delivered rectally, bucally or by insufflation.

Determination of the proper dosage for a particular situation is withinthe skill of the practitioner. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired. A typical dose is about 1 mg to about 1,000 mg perday, such as about 5 mg to about 500 mg per day. In certain embodiments,the dose is about 10 mg to about 300 mg per day, such as about 25 mg toabout 250 mg per day.

V. Chemistry

Abbreviations

For convenience, the following common abbreviations are used herein:

LCMS for Liquid Chromatography-Mass Spectrometry.

HPLC for High Pressure Liquid Chromatography.

NMR for Nuclear Magnetic Resonance.

RT for Retention Time.

MI for Molecular Ion

h for hours

min for minutes

AlCl₃ for aluminium chloride

BBr₃ for boron tribromide

Boc for tert-butoxycarbonyl

cataCXium C fortrans-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II).

Cs₂CO₃ for cesium carbonate

CuI for copper(I)iodide

DAST for diethylaminosulfur trifluoride

DBU for 1,8-diazabicyclo(5.4.0)undec-7-ene

DMAP for 4-(dimethylamino) pyridine

DCE for 1,1-dichloroethane or ethylidene chloride

DCM for dichloromethane or methylene chloride

DEA for diethanolamine

DIPEA for N,N,-di-isopropyethylamine, Hunig's base

DMA for N,N-dimethylacetamide

DMF for N,N-dimethylformamide

DMSO for dimethylsulfoxide.

Et₃N for triethylamine

EtOH for ethyl alcohol, ethanol

HCl for hydrochloric acid

H₂SO₄ for sulfuric acid

KOH for potassium hydroxide

MW for microwave

mCPBA for meta-Chloroperoxybenzoic acid

MeOH for methyl alcohol, methanol

Mo(CO)₆ for Molybdenum hexacarbonyl

MP-BH₄ for macroporous triethylammonium methyl polystyrene borohydride

NaOH for sodium hydroxide

Na₂CO₃ for sodium carbonate

Na₂SO₄ for sodium sulphate

NaOAc for sodium acetate

NaOtBu for sodium t-butoxide

NMP for 1-methyl-2-pyrrolidinone

NMM for N-methylmorpholine

Pd(dba)₂ for Bis(dibenzylideneacetone)palladium

Pd(OAc)₂ for Palladium diacetate

Pd(Ph₃)₄ for tetrakis(triphenylphosphine)palladium

Pd(PPh₃)₂Cl₂ for Bis(triphenylphosphine)palladium(II) dichloride

POCl₃ for phosphorus oxychloride

PPh₃ for triphenylphosphine

PS-TsCl for polystyrene sulfonyl chloride

PS-PPh₃-Pd for polystyrene triphenylphosphine-Pd(0)

SCX-2 for a silica-based sorbent with a chemically bonded propylsulfonicacid functional group

TBAF for Tetra-n-butylammonium fluoride

TBDMS for tert-butyldimethylsilyl

TCA for trichloroacetic acid

TFA for trifluoroacetic acid

THF for tetrahydrofuran

TMS azide for trimethylsilyl azide

Xantphos for 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

XPhos for 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

NMR

Proton NMR spectra are recorded using a Bruker AMX-300 NMR machine at300 MHz or a Bruker Avance NMR machine at 400 MHz. Shifts are reportedin ppm values relative to an internal standard of tetramethylsilane(TMS) or residual protic solvent. The following abbreviations are usedto describe the splitting patterns: s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), dd (double-doublet), dt(double-triplet), br (broad).

LCMS Methods

Samples analysed by High Performance Liquid Chromatography-MassSpectrometry employed the following conditions.

Method 1

Method 1 employed Gilson 306 pumps, Gilson 811C mixer, Gilson 806manometric module, and Gilson UV/VIS 152 detector at 254 nm wavelength.The mass spectrometer was a Finnigan AQA and the column used was aWaters SunFire, 5 μm pore size, C18 of dimensions 50×4.60 mm. Theinjection volume was 10 μl.

The mobile phase consisted of a mixture of water and acetonitrilecontaining 0.1% formic acid. The eluent flow rate was 1.5 mL/min, using95% water: 5% acetonitrile, changed linearly to 5% water: 95%acetonitrile over 5.5 minutes and then maintained at this mixture for 2minutes.

Method 2

Method 2 employed Waters 515 pumps, a Waters 2525 mixer and a Waters2996 diode array detector. The detection was performed between 210 nmand 650 nm. The mass spectrometer was a Waters micromass ZQ and thecolumn used was a Waters SunFire, 5 μm pore size, C18 of dimensions50×4.60 mm. The injection volume was 10 μl.

The mobile phase consisted of a mixture of water and acetonitrilecontaining 0.1% formic acid. The eluent flow rate was 1.5 mL/min, using95% water: 5% acetonitrile, changed linearly to 5% water: 95%acetonitrile over 5.5 minutes and then maintained at this mixture for 2minutes.

Method 3

Method 3 employed Waters 515 pumps, a Waters 2525 mixer and a Waters2487 UV detector (single wavelength 254 nm). The mass spectrometer was aWaters micromass ZQ and the column used was a Waters SunFire, 5 μm poresize, C18 of dimensions 50×4.60 mm. The injection volume was 10 μl. Themobile phase consisted of a mixture of water and acetonitrile containing0.1% formic acid. The eluent flow rate was 1.5 mL/min, using 95% water:5% acetonitrile, changed linearly to 5% water: 95% acetonitrile over 5.5minutes and then maintained at this mixture for 2 minutes.

Method 4

Method 4 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was performed between 210 nm and 650 nm. Themass spectrometer used was a Waters 3100 which detected masses between100 and 700 g/mol. The column used was a XBridge, 5 micron pore size,C18, 50×4.60 mm. The injection volume was 10 μl of a solution (around 1mg/ml). The flow rate was 1.5 mL/min and the mobile phases of water pH10 0.03% ammonium hydroxide) (3 ml/101) and acetonitrile 0.03% ammoniumhydroxide (3 ml/101). The elution was started at 95% water: 5%acetonitrile ramping up to 5% water:95% acetonitrile over 5.50 minutes.The eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 6 seconds. These conditions were held for 1.4minutes to allow equilibration of the column before the next sample wasinjected. The run lasted 7 minutes in total.

Method 5

Method 5 employed Waters 515 pumps, a Waters 2525 mixer with valvesdirecting to the different columns and a Waters 2487 UV detector. Thedetection was done between at 254 nm. The mass spectrometer used was aWaters micromass ZQ which detected masses between 100 and 700 g/mol. Thecolumn used was a SunFire, 5 micron pore size, C18 column of dimensions50×4.60 mm was used. The injection volume was 10 μL of a solution(around 1 mg/mL). The flow rate was 1.5 mL/min and the mobile phases ofwater and methanol contained 0.1% formic acid. The elution was startedat 85% water: 15% methanol ramping up to 15% water:85% methanol over 4.5minutes, these conditions were held for 1 minute before the eluent levelwas returned to the starting conditions of 85% water: 15% methanol over6 seconds. These conditions were held for 1.4 minutes to allowequilibration of the column before the next sample was injected. The runlasted 7 minutes in total.

Method 6

Method 6 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was done between 210 nm and 650 nm. The massspectrometer used was a Waters 3100 which detected masses between 100and 700 g/mol. The column used was a XBridge, 5 micron pore size, C18,50×4.60 mm. The injection volume was 10 μL of a solution (around 1mg/mL). The flow rate was 1.5 mL/min and the mobile phases of water pH10 0.03% ammonium hydroxide) (3 ml/101) and methanol 0.03% ammoniumhydroxide (3 ml/101). The elution was started at 85% water: 15% methanolramping up to 15% water: 85% methanol over 4.5 minutes. These conditionswere held for 1 minute before the eluent level was returned to thestarting conditions of 85% water: 15% methanol over 6 seconds. Theseconditions were held for 1.4 minutes to allow equilibration of thecolumn before the next sample was injected. The run lasted 7 minutes intotal.

Method 7

Method 7 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2487 UV detector. Thedetection was done between at 254 nm. The mass spectrometer used was aWaters micromass ZQ which detected masses between 100 and 700 g/mol. Thecolumn used was a SunFire, 5 micron pore size, C18 column of dimensions50×4.60 mm was used. The injection volume was 10 μL of a solution(around 1 mg/mL). The flow rate was 1.5 mL/min and the mobile phases ofwater and methanol contained 0.1% formic acid. The elution was startedat 85% water: 15% methanol ramping up to 15% water:85% methanol over 4.5minutes, these conditions were held for 1 minute before the eluent levelwas returned to the starting conditions of 85% water: 15% methanol over6 seconds. These conditions were held for 1.4 minutes to allowequilibration of the column before the next sample was injected. The runlasted 7 minutes in total.

Method 8

Method 8 employed Waters 515 pumps, a Waters 2525 mixer with valvesdirecting to the different columns and a Waters 2487 UV detector. Thedetection was done between at 254 nm. The mass spectrometer used was aWaters micromass ZQ which detected masses between 100 and 700 g/mol. Thecolumn used was a SunFire, 5 micron pore size, C18 column of dimensions50×4.60 mm was used. The injection volume was 10 μL of a solution(around 1 mg/mL). The flow rate was 1.5 mL/min and the mobile phases ofwater and methanol contained 0.1% formic acid. The elution was startedat 85% water: 15% methanol ramping up to 15% water:85% methanol over 3minutes, these conditions were held for 2.5 minute before the eluentlevel was returned to the starting conditions of 85% water: 15% methanolover 6 seconds. These conditions were held for 1.4 minutes to allowequilibration of the column before the next sample was injected. The runlasted 7 minutes in total.

Method 9

Method 9 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2487 UV detector. Thedetection was done between at 254 nm. The mass spectrometer used was aWaters micromass ZQ which detected masses between 100 and 700 g/mol. Thecolumn used was a XBridge, 5 micron pore size, C18, 50×4.60 mm. Theinjection volume was 10 μL of a solution (around 1 mg/mL). The flow ratewas 1.5 mL/min and the mobile phases of water pH 10 0.03% ammoniumhydroxide) (3 ml/101) and methanol 0.03% ammonium hydroxide (3 ml/10 l).The elution was started at 85% water: 15% methanol ramping up to 15%water: 85% methanol over 4.5 minutes. These conditions were held for 1minute before the eluent level was returned to the starting conditionsof 85% water: 15% methanol over 6 seconds. These conditions were heldfor 1.4 minutes to allow equilibration of the column before the nextsample was injected. The run lasted 7 minutes in total.

Method 10

LCMS results were obtained on either of two instruments. LCMS analysiswas performed on a Waters Aquity Ultra Performance LC with a 2.1 mm×50mm Waters Aquity UPLC BEH C18 1.7 μm column. The target columntemperature was 45° C., with a run time of two (2) minutes, a flow rateof 0.600 mL/min, and a solvent mixture of 5% (0.1% formicacid/water):95% (acetonitrile/0.1% formic acid). The mass spectrometrydata was acquired on a Micromass LC-ZQ 2000 quadrupole massspectrometer. Alternatively, LCMS analysis was performed on a BrukerEsquire 200 ion trap.

Preparative HPLC Methods

Samples purified by Mass Spectrometry directed High Performance LiquidChromatography employed the following conditions.

Method A

Method A employed Waters 515 pumps, a Waters 2525 mixer and a Waters2487 UV detector (single wavelength 254 nm). The mass spectrometer was aWaters micromass ZQ and the column used was a Waters SunFire, 5 μm poresize, C18 of dimensions 50×19 mm. The injection volume was up to 500 μLof solution at a maximum concentration of 50 mg/mL. The mobile phaseconsisted of a mixture of water and acetonitrile containing 0.1% formicacid. The eluent flow rate was 25 mL/min using 95% water, 5%acetonitrile, changing linearly over 5.3 minutes to 95% acetonitrile, 5%water, and maintaining for 0.5 minutes.

Method B

Method B employed Waters 515 pumps a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was performed between 210 nm and 650 nm. Themass spectrometer used was a Waters 3100 which detected masses between100 and 700 g/mol. The column used was a XBridge, 5 micron pore size,C18, 50×19 mm. The injection volume was chosen by the user and can be upto 500 μL of the solution (max 50 mg/mL). The flow rate was 25 mL/minand the mobile phases of water pH 10 0.03% ammonium hydroxide (3 ml/101)and acetonitrile 0.03% ammonium hydroxide (3 ml/101). The elution wasstarted at 95% water:5% acetonitrile ramping up to 5% water:95%acetonitrile over 5.30 minutes. The eluent level was returned to thestarting conditions of 95% water: 5% acetonitrile over 0.6 minutes.These conditions were held for 1.4 minutes to allow equilibration of thecolumn before the next sample was injected. The run lasted 7 minutes intotal.

Analytical HPLC Methods

Method X

Method X employs gradient elution (0 to 100%) acetonitrile (containing0.1% trifluoroacetic acid):water (containing 0.1% trifluoroacetic acid)over five minutes on a 4.6×75 mm (2.5 micron) Zorbax XDB-C8 column at2.5 ml/min on an Agilent 1100 series HPLC.

Synthesis

Several methods for the chemical synthesis of4-substituted-2-(pyridin-4-yl)-thieno[2,3-d]pyrimidine compounds(“4PT23P compounds”) and4-substituted-2-(pyridin-4-yl)-thieno[3,2-d]pyrimidine compounds(“4PT32P compounds”) of the present invention are described herein.These and/or other well known methods may be modified and/or adapted inknown ways in order to facilitate the synthesis of additional compoundswithin the scope of the present invention. Unless otherwise stated,compounds are of commercial origin or readily synthesized by standardmethods well known to one skilled in the art of organic synthesis.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this invention. Specificchemical transformations are listed in the ensuing schemes and oneskilled in the art appreciates that a variety of different reagents maybe used in place of those listed. Common replacements for such reagentscan be found in texts such as “Encyclopedia of Reagents for OrganicSynthesis” Leo A. Paquette, John Wiley & Son Ltd (1995) or“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations” Richard C. Larock. Wiley-VCH and “Strategic Applicationsof Named Reactions in Organic Synthesis” Kurti and Czako, Elsevier, 2005and references cited therein.

4PT23P Compounds

In one approach, compounds of formula [F-1] (where A=NH or N alkyl) areprepared by reacting a compound of formula [F-2] (where X is a halogensuch as chlorine or sulfonate) with a compound of formula [F-3] (where Ais NH or NH₂ and Z on the terminal nitrogen is H, alkyl or a suitablenitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc) in asuitable solvent such as DMF in the presence of a suitable base such astriethylamine.

The reaction is suitably conducted at an elevated temperature forexample 40° C. Where Z is a suitable nitrogen protecting group, such asBoc, Alloc, Cbz or Fmoc, compounds of formula [F-1] are prepared by asuitable deprotection reaction. For example: where Z is a Boc protectinggroup reaction with an acid such as TFA in a suitable solvent such asDCM. The reaction is suitably conducted at ambient temperature. In oneapproach, compounds of formula [F-1] (where A is O) are prepared byreacting a compound of formula [F-2] (where X is a halogen such aschlorine or sulfonate) with a compound of formula [F-2] (where A=OH andZ on the terminal nitrogen is H, alkyl or a suitable nitrogen protectinggroup, such as Boc, Alloc, Cbz or Fmoc) in a suitable solvent such asDMA in the presence of a suitable base such as sodium hydride. Thereaction is suitably conducted at ambient temperature. Where Z is asuitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc,compounds of formula [F-1] are prepared by a suitable deprotectionreaction. For example: where Z is a Boc protecting group reaction withan acid such as TFA in a suitable solvent such as DCM. The reaction issuitably conducted at ambient temperature.

In one approach, compounds of formula [F-2] (where X is a halogen suchas chlorine) are prepared by reacting a compound of formula [F-4] with asuitable halogenating agent such as phosphorous oxychloride. Thereaction is suitably conducted at elevated temperature such as 125° C.Compounds of formula [F-2](where X is a sulfonate) are prepared byreacting a compound of formula [F-4] with a suitably substitutedsulfonyl chloride such as 2,4,6-triisopropylbenzenesulfonyl chloride ina suitable solvent such as DMA in the presence of a suitable base suchas triethylamine and a catalytic amount of DMAP. The reaction issuitably conducted at ambient temperature.

In one approach, compounds of formula [F-4] are prepared by reacting acompound of formula [F-5] (where Rx is an alkyl group such as methyl orethyl) with a compound of formula [F-6] in a suitable solvent such asdioxane with a suitable base such as potassium-tert-pentylate. Thereaction is suitably conducted at ambient temperature.

In one approach, compounds of formula [F-5] are prepared by reacting aketone derivative of formula [F-7] (where R^(x1) and R^(x2) are H,alkyl, aryl or form a cyclic saturated ring) with a cyanoacetic acidderivative of formula [F-8] (where Rx is an alkyl group such as methylor ethyl) with elemental sulphur in the presence of a base such asmorpholine in a suitable solvent such as ethanol. The reaction issuitably conducted at an elevated temperature for example 80-90° C.

In one approach, compounds of formula [F-3] (where A is OH) are preparedby reacting a compound of formula [F-9] (where Z on the terminalnitrogen is H, alkyl or a suitable nitrogen protecting group, such asBoc, Alloc, Cbz or Fmoc) with a reducing agent such as borane-THFcomplex in a suitable solvent such as THF. The reaction is suitablyconducted at low temperature for example 0° C. In one approach,compounds of formula [F-3] (where A is NH₂) are prepared by reacting acompound of formula [F-10] (where Z on the terminal nitrogen is H, alkylor a suitable nitrogen protecting group, such as Boc, Alloc, Cbz orFmoc) with a reducing agent such as borane-THF complex in a suitablesolvent such as THF. The reaction is suitably conducted at lowtemperature for example 0° C. In one approach, compounds of formula[F-10] are prepared by reacting compounds of formula [F-9] with Bocanhydride in the presence of a suitable base such as pyridine, ammoniumcarbonate in a suitable solvent such as dioxane. The reaction issuitably conducted at ambient temperature.

An example of a method as described above is illustrated in thefollowing scheme.

General Synthesis of 2-amino-4,5-substituted-thiophene-3-carboxylic acidethyl esters of general formula [F-5] (Scheme A1)

2-amino-4,5-substituted-thiophene-3-carboxylic acid ethyl esters ofgeneral formula [F-5] were synthesised by a cyclisation reaction withcyano-acetic acid ethyl ester of general formula [F-8], a substitutedketone of general formula [F-7] and elemental sulphur in the presence ofmorpholine in a polar protic solvent such as ethanol at reflux (schemeA1).

Synthesis of2-Amino-1,4-Dioxa-spiro[6.6]4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylicacid ethyl ester [AA-1]

To a mixture of 1,4-Dioxa-spiro[4.5]decan-8-one (1.56 g, 10 mmol),cyano-acetic acid ethyl ester (1.13 g, 10 mmol) and elemental sulphur(320 mg, 10 mmol) in ethanol (20 ml) was added morpholine (870 mg, 10mmol). The reaction was heated at reflux overnight. The mixture was leftto cool down and a precipitate formed which was recovered by filtrationand washed with cold ethanol (40 ml), then dried under reduced pressureto give the title compound (2.1 g, 76%) which was used without furtherpurification. LCMS method: 3, RT: 5.24 min, MI: 284 [M+1]. 1H NMR (300MHz, DMSO): 4.21 (m, 1H), 4.17 (q, 2H), 4.01 (m, 1H), 3.82 (m, 2H), 3.08(m, 1H), 2.68 (m, 1H), 1.91 (m, 4H), 1.21 (t, 3H).

Synthesis of2-amino-6,6-dimethyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylicacid ethyl ester [AA-2]

To a mixture of 4,4-Dimethyl-cyclohexanone, cyano-acetic acid ethylester and elemental sulphur in ethanol was added morpholine. Thereaction was reflux overnight. The mixture was left to cool down and aprecipitate appeared. The solid was recovered by filtration and to givethe title compound as a yellow solid. LCMS method: 3, RT: 5.64 min, MI:254 [M+1].

Synthesis of 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylicacid ethyl ester [AA-3]

To a mixture of tetrahydro-thiopyran-4-one, cyano-acetic acid ethylester and elemental sulphur in ethanol was added morpholine. Thereaction was reflux overnight. The mixture was left to cool down and aprecipitate appeared. The solid was recovered by filtration and to givethe title compound as a yellow solid. LCMS method: 3, RT: 5.78 min, MI:244 [M+1].

Synthesis of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acidethyl ester [AA-4]

To a mixture of tetrahydro-pyran-4-one, cyano-acetic acid ethyl esterand elemental sulphur in ethanol was added morpholine. The reaction wasreflux overnight. The mixture was left to cool down and a precipitateappeared. The solid was recovered by filtration and to give the titlecompound as a yellow solid. LCMS method: 3, RT: 5.86 min, MI: 228 [M+1].

General Synthesis of 5,6-substituted 2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ols of General Formula [F-4] (Scheme A2)

4,5-substituted-2-amino-thiophene-3-carboxylic acid alkyl esters ofgeneral formula [F-5] were subjected to a cyclisation reaction with4-cyanopyridine of general formula [F-6] in the presence of a hinderedalkoxide base such as potassium-tert-pentylate 1.7M in toluene orpotassium-tert-butoxide in a dry non-aprotic solvent such as dioxane orTHF at ambient temperature.

Synthesis of2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-5]

To a solution of 4-cyanopyridine (1.25 g, 12 mmol) in dry dioxane (10ml) was added 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylicacid ethyl ester (2.25 g, 10 mmol) followed by potassium-tert-pentylate1.7M in toluene (12 ml, 20 mmol). The reaction mixture was stirred atroom temperature overnight. After completion the precipitate formed wasfiltered and washed with diethyl ether. The residue was used without anyfurther purification in the next step. LCMS method: 1, RT: 3.54 min, MI:284 [M+1]. 1H 1H NMR (300 MHz, DMSO): 8.56 (d, 2H), 8.12 (d, 2H), 2.90(m, 2H), 2.67 (m, 2H), 1.76 (m, 4H). The following compounds wereprepared according to the general synthesis shown in scheme A2:

7-methyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-6] was prepared by reaction of2-amino-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acidethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as anoff-white solid. LCMS method: 1, RT: 3.68 min, MI: 298 [M+1].

2-pyridin-4-yl-5,6,7,8,9,10-hexahydro-11-thia-1,3-diaza-cycloocta[a]inden-4-ol[AA-7] was prepared by reaction of2-amino-4,5,6,7,8,9-hexahydro-cycloocta[b]thiophene-3-carboxylic acidethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as anoff-white solid. LCMS method: 1, RT: 3.72 min, MI: 312 [M+1].

2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ol[AA-8] was prepared by reaction of2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acidethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as a yellowsolid. LCMS method: 2, RT: 3.87 min, MI: 298 [M+1].

1,4-Dioxa-spiro[7.7]-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-9] was prepared by reaction of2-Amino-1,4-Dioxa-spiro[6.6]4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylicacid ethyl ester [AA-1], 4-cyanopyridine, potassium-tert-pentylate 1.7Min toluene and dioxane at room temperature to give the title compound asa yellow solid. LCMS method: 3, RT: 2.80 min, MI: 342 [M+1].

7,7-dimethyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-10] was prepared by reaction of2-amino-6,6-dimethyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylicacid ethyl ester [AA-2], 4-cyanopyridine, potassium-tert-pentylate 1.7Min toluene and dioxane at room temperature to give the title compound asan off-white solid. LCMS method: 3, RT: 4.24 min, MI: 312 [M+1].

4-hydroxy-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylicacid tert-butyl ester [AA-11] was prepared by reaction of2-amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid6-tert-butyl ester 3-ethyl ester, 4-cyanopyridine,potassium-tert-pentylate 1.7M in toluene and dioxane at room temperatureto give the title compound as an off-white solid. LCMS method: 1, RT:3.50 min, MI: 384 [M+1].

2-pyridin-4-yl-5,8-dihydro-6H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ol[AA-12] was prepared by reaction of2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid ethyl ester[AA-4], 4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene anddioxane at room temperature to give the title compound as a yellowsolid. LCMS method: 3, RT: 3.50 min MI: 286 [M+1].

2-pyridin-4-yl-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ol[AA-13] was prepared by reaction of2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylic acid ethylester [AA-3], 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as a yellowsolid. LCMS method: 2, RT: 3.14 min, MI: 302 [M+1].

(4-Hydroxy-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7-yl)-phenyl-methanone[AA-14] was prepared by reaction of2-Amino-6-benzoyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid ethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M intoluene and THF at room temperature to give the title compound as ayellow solid. LCMS method: 3, RT: 3.02 min, MI: 389[M+1].

5-Methyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-15] was preparedby reaction of ethyl 2-amino-4-methylthiophene-3-carboxylate,4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and THF atroom temperature to give the title compound as a yellow solid. LCMSmethod: 3, RT: 2.56 min, MI: 244[M+1].

5-isobutyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-16] wasprepared by reaction of 2-amino-4-isobutyl-thiophene-3-carboxylic acidethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as a brownsolid. LCMS method: 2, RT: 3.14 min, MI: 286 [M+1].

5-ethyl-6-methyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-17] wasprepared by reaction of 2-amino-4-ethyl-5-methyl-thiophene-3-carboxylicacid ethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M intoluene and dioxane at room temperature to give the title compound as abrown solid. LCMS method: 2, RT: 3.26 min, MI: 272 [M+1].

6-ethyl-2-pyridin-4-yl-thieno [2,3-d]pyrimidin-4-ol [AA-18] was preparedby reaction of 2-amino-5-ethyl-thiophene-3-carboxylic acid ethyl ester,4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and dioxane atroom temperature to give the title compound as a brown solid. LCMSmethod: 2, RT: 3.15 min, MI: 258 [M+1].

5,6-dimethyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-19] wasprepared by reaction of 2-amino-4,5-dimethyl-thiophene-3-carboxylic acidethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as a yellowsolid. LCMS method: 3, RT: 3.05 min, MI: 258 [M+1].

4-hydroxy-5-methyl-2-pyridin-4-yl-thieno [2,3-d]pyrimidine-6-carboxylicacid amide [AA-20] was prepared by reaction of2-amino-5-carbamoyl-4-methyl-thiophene-3-carboxylic acid ethyl ester,4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and dioxane atroom temperature to give the title compound as a brown solid. LCMSmethod: 2, RT: 3.02 min, MI: 287 [M+1].

6-isopropyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-21] wasprepared by reaction of 2-amino-5-isopropyl-thiophene-3-carboxylic acidethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as a brownsolid. LCMS method: 2, RT: 3.29 min, MI: 272 [M+1].

6-methyl-5-phenyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-22] wasprepared by reaction of 2-amino-5-methyl-4-phenyl-thiophene-3-carboxylicacid ethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M intoluene and dioxane at room temperature to give the title compound as ayellow solid. LCMS method: 2, RT: 3.79 min, MI: 320 [M+1].

5-(4-bromo-phenyl)-2-pyridin-4-yl-thieno [2,3-d]pyrimidin-4-ol [AA-23]was prepared by reaction of2-amino-4-(4-bromo-phenyl)-thiophene-3-carboxylic acid ethyl ester,4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and dioxane atroom temperature to give the title compound as a brown solid. LCMSmethod: 2, RT: 4.16 min, MI: 384-386 [M+1].

General Synthesis of 5,6 Substituted4-amino-2-pyridin-4-yl-thieno[2,3-d]pyrimidines of General Formula [F-1](Scheme A3)

5,6-substituted 2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol derivativesof general formula [F-4] were reacted in an activation step using achlorinating reagent such as phosphorus oxychloride or phosphorouspentachloride to yield the 5,6-substituted4-chloro-2-pyridin-4-yl-thieno[2,3-d]pyrimidine derivatives of generalformula [F-11], which were reacted with primary or secondary aminederivative of general formula [F-13] at ambient temperature. Afterreaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the crude reactionproduct was purified by reverse phase preparative HPLC.

Synthesis of4-chloro-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[AA-24]

2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-5] (1 g, 3.6 mmol) was stirred in POCl₃ (10 ml, 109 mmol) at refluxat 125° C. overnight. The mixture was allowed to cool down to roomtemperature and the excess of POCl₃ was removed under reduced pressure.The residue was carefully poured into ice-water and the solution wasbasified with a saturated solution of sodium hydrogen carbonate (50 ml)and the product was extracted into DCM (2×25 ml). The combined extractswere dried with magnesium sulfate, filtered and evaporated under reducedpressure to yield the title compound as a yellow-orange solid, which wasused without further purification. LCMS method: 2, RT: 5.46 min, MI: 302[M+1].

Synthesis ofN,N-dimethyl-N′-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2-diamine[1]

To a solution of4-chloro-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine(50 mg, 0.166 mmol) [AA-24] in DMA (1 ml) was addedN,N-dimethylethylenediamine (20 μl, 0.166 mmol) followed by Et₃N (32 μl,0.232 mmol) and the mixture was stirred at room temperature for 2 hours.The reaction mixture was loaded onto a SCX-2 cartridge, and washed withmethanol. The product was released from the cartridge using a solutionof 2M ammonia/methanol. The ammonia/methanol eluent was concentratedunder reduced pressure and the crude product was purified by preparativeHPLC (method A) to yield to the title compound. LCMS method: 2: RT: 2.1min, MI: 354 [M+1]. 1H NMR (300 MHz, DMSO): 8.70 (d, 2H) 8.20 (d, 2H),3.7 (m, 2H), 2.9 (m, 2H), 2.8 (m, 2H), 2.6 (m, 2H), 2.3 (s, 6H), 1.8 (m,4H).

The following compounds were prepared according to the general synthesisshown in scheme A3:

Amine Ex SM [F-13] Characterisation  2 [AA- 24]

method: 2, RT: 2.05 min, MI: 340 [M + 1]  3 [AA- 24]

method: 2, RT: 2.13 min, MI: 352 [M + 1]  4 [AA- 24]

method: 2, RT: 2.15 min, MI: 380 [M + 1] 1H NMR (300 MHz, DMSO): 8.70(d, 2H) 8.20 (d, 2H), 4 (m, 2H), 3.8 (m, 2H), 3.2 (m, 2H), 3 (m, 2H),2.9 (m, 4H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H), 0.8 (s, 3H)  5 [AA-24]

method: 2, RT: 2.10 min, MI: 340 [M + 1]  6 [AA- 24]

method: 2, RT: 2.33 min, MI: 400 [M + 1]  7 [AA- 24]

method: 2, RT: 2.46 min, MI: 455 [M + 1]  8 [AA- 24]

method: 2, RT: 2.20 min, MI: 366 [M + 1]  9 [AA- 24]

method: 2, RT: 2.23 min, MI: 380 [M + 1] 10 [AA- 24]

method: 2, RT: 2.30 min, MI: 380 [M + 1] 1H NMR (300 MHz, DMSO): 8.8 (d,2H), 8.2 (d, 2H), 3.4 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 2.90 (m, 2H),2.68 (m, 2H), 1.9 (m, 4H), 1.13 (d, 6H) 11 [AA- 24]

method: 2, RT: 2.10 min, MI: 338 [M + 1]

General Synthesis of 5,6 Substituted4-amino-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-1] (Scheme A4)

5,6 substituted 4-chloro-2-pyridin-4-yl-thieno[2,3-d]pyrimidinederivatives of general formula [F-11] were reacted with N-Boc protectedprimary or secondary diamine derivatives of general formula [F-13] atambient temperature. After reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release,

the N-Boc derivatives were deprotected under acidic conditions with astrong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in asolvent such as DCM, DCE, THF, EtOH or MeOH and, the crude reactionproduct was purified by reverse phase preparative HPLC

Synthesis ofN*1*-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2-diamine[12]

To a solution of4-chloro-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine(50 mg, 0.166 mmol) [AA-24] in DMA (1 ml) was added(2-amino-ethyl)-carbamic acid tert-butyl ester (28 μl, 0.182 mmol)followed by Et₃N (32 μl, 0.232 mmol), the mixture was stirred at roomtemperature for 2 hours. The product was extracted with DCM (1 ml) andwashed with brine (2 ml). To the organic phase was added TFA (1 ml) andthe mixture was stirred at room temperature for 1 hour. After completionthe mixture was loaded onto a SCX-2 cartridge and washed with methanol.The product was released from the cartridge using a solution of 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the crude product was purified by preparative HPLC(method A) to yield to the title compound. LCMS method: 2, RT: 2.07 min,MI: 326 [M+1]. 1H NMR (300 MHz, DMSO): 8.70 (d, 2H), 8.28 (d, 2H), 3.88(m, 2H), 3.14 (m, 2H), 2.94 (m, 2H), 2.78 (m, 2H), 1.84 (m, 4H).

The following compounds were prepared according to the general synthesisshown in Scheme A4:

Amine Ex SM [F-13] Characterisation 13 [AA- 5]

method: 2, RT: 2.05 min, MI: 340 1H NMR (300 MHz, DMSO): 8.7 (d, 2H),8.2 (d, [M + 1] 2H), 3.9 (m, 2H), 3.1 (m, 2H), 3 (m, 2H), 2.8 (m, 2H),2.45 (s, 3H), 1.8 (m, 4H) 14 [AA- 5]

method 2, RT: 2.10 min, MI: 366 [M + 1] 15 [AA- 5]

method: 2, RT: 2.17 min, MI: 340 [M + 1] 16 [AA- 5]

method: 2, RT: 2.35 min, MI: 382 [M + 1] 17 [AA- 5]

method: 2, RT: 2 18 min, MI: 354 [M + 1] 18 [AA- 5]

method: 2, RT: 2.13 min, MI: 364 [M + 1]

General Synthesis of 5,6-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester Derivatives ofGeneral Formula [F-12] (Scheme A5)

Compounds were prepared by the reaction of 5,6-substituted2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol derivatives of generalformula [F-4] (described in scheme A2) with2,4,6-triisopropylbenzenesulfonyl chloride in halogenated solvent suchas DCM or a polar aprotic solvent such as DMA, DMF, NMP with a tertiaryalkylamine base such as Et₃N, DIPEA or NMM and a catalytic amount ofDMAP.

Synthesis of 2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-25]

To a solution of2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol(1 g, 3.5 mmol) [AA-5] in DCM (10 ml) was added2,4,6-triisopropylbenzenesulfonyl chloride (1.3 g, 4.2 mmol), Et₃N (1.5ml, 10.5 mmol) and DMAP (6 mg, 0.05 mmol). The mixture was stirred forat room temperature for one hour. After completion the mixture wasdiluted with water and the product was extracted into DCM (2×2 ml). Thecombined extracts were dried with magnesium sulfate, filtered andevaporated under reduced pressure to yield the title compound as a brownsolid, which was used without further purification in the next step.LCMS method: 3, RT: 6.23 min, MI: 550 [M+1].

The following compounds were prepared according to the general synthesisshown in scheme A5:

2,4,6-triisopropyl-benzenesulfonic acid7-methyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-26] was prepared by reaction of7-methyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-6], 2,4,6-triisopropyl benzene sulfonyl chloride, Et₃N, DMAP and DCMat room temperature to give the desired compound as a brown solid. LCMSmethod: 3, RT: 6.34 min, MI: 564 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8,9,10-hexahydro-1-thia-1,3-diaza-cycloocta[a]inden-4-ylester [AA-27] was prepared by reaction of2-pyridin-4-yl-5,6,7,8,9,10-hexahydro-11-thia-1,3-diaza-cycloocta[a]inden-4-ol[AA-7], 2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCMat room temperature to give the desired compound as a brown solid. LCMSmethod: 3, RT: 6.47 min, MI: 578 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ylester [AA-28] was prepared by reaction of2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ol[AA-8], 2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCMat room temperature to give the title compound as a brown solid. LCMSmethod: 3, RT: 6.39 min, MI: 564 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid1,4-Dioxa-spiro[7.7]-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-olester [AA-29] was prepared by reaction of1,4-Dioxa-spiro[7.7]-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-9], 2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCMat room temperature to give the desired compound as a brown solid. LCMSmethod: 3, RT: 6.56 min, MI: 608 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid7,7-dimethyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-30] was prepared by reaction of7,7-dimethyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol[AA-10], 2,4,6-triisopropyl benzenesulfonyl chloride, Et₃N, DMAP and DCMat room temperature to give the desired compound as a brown solid. LCMSmethod: 3, RT: 6.37 min, MI: 578 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,8-dihydro-6H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl ester [AA-31] was prepared by reaction of2-pyridin-4-yl-5,8-dihydro-6H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ol[AA-12], 2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCMat room temperature to give the desired compound as a brown solid. LCMSmethod: 3, RT: 6.29 min, MI: 552 [M+1].

2,4,6-Triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-32] was prepared by reaction of2-pyridin-4-yl-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ol[AA-13], 2,4,6-triisopropyl benzene sulfonyl chloride, Et₃N, DMAP andDCM at room temperature to give the desired compound as a brown solid.LCMS method: 3, RT: 6.58 min, MI: 568 [M+1].

2,4,6-Triisopropyl-benzenesulfonic acid7-benzoyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-33] was prepared by reaction of(4-Hydroxy-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7-yl)-phenyl-methanone[AA-14], 2,4,6-triisopropyl benzene sulfonyl chloride, Et₃N, DMAP andDCM at room temperature to give the desired compound as a brown solid.LCMS method: 3, RT: 6.67 min, MI: 655 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid5-isobutyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester [AA-34] wasprepared by reaction of5-Isobutyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-16],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.36 min, MI: 552 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid5-ethyl-6-methyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester[AA-35] was prepared by reaction of5-ethyl-6-methyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-17],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.29 min, MI: 538 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid 6-ethyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester [AA-36] was prepared by reaction of6-ethyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-18],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.22 min, MI: 524 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid5,6-dimethyl-2-pyridin-4-yl-thieno [2,3-d]pyrimidin-4-yl ester [AA-37]was prepared by reaction of5,6-dimethyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-19],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.18 min, MI: 524 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid6-carbamoyl-5-methyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester[AA-38] was prepared by reaction of4-hydroxy-5-methyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidine-6-carboxylicacid amide [AA-20], 2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N,DMAP and DCM at room temperature to give the desired compound as a brownsolid. LCMS method: 3, RT: 6.12 min, MI: 553 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid6-isopropyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester [AA-39] wasprepared by reaction of6-isopropyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-21],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.24 min, MI: 538 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid6-methyl-5-phenyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester[AA-40] was prepared by reaction of6-methyl-5-phenyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-22],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.55 min, MI: 586 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid5-(4-bromo-phenyl)-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester[AA-41] was prepared by reaction of5-(4-bromo-phenyl)-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-ol [AA-23],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.66 min, MI: 651 [M+1].

General Synthesis of 5,6 Substituted4-amino-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-1] (Scheme A6)

5,6-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester derivatives ofgeneral formula [F-12] [prepared in scheme A5] were reacted with aprimary or secondary amino derivative of general formula [F-13] in apolar aprotic solvent such as DMA, DMF, NMP in the presence of atertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature.After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativeswere deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction product was purified by reversephase preparative HPLC

(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine[19]

To a solution of 2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester (60 mg, 0.110 mmol) [AA-25] in DMA (1 ml) was added(R)-(+)-1-Boc-3-aminopyrrolidine (23 mg, 0.121 mmol) followed by Et₃N(30 μl, 0.220 mmol) and the mixture was stirred at room temperature for2 hours. Water (1 ml) was added and the mixture was extracted with DCM(2×ml), the extracts were combined and washed with brine (2 ml). To theorganic phase was added TFA (1 ml) and the mixture was stirred at roomtemperature for 1 hour. After completion the mixture was loaded onto aSCX-2 cartridge and washed with methanol. The product was released fromthe cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method B) to yield tothe desired compound. LCMS method: 4, RT: 4.43 min, MI: 352 [M+1]. 1HNMR (300 MHz, DMSO): 8.70 (d, 2H), 8.24 (d, 2H), 3.53 (m, 2H), 3.33 (m,1H), 3.22 (m, 2H), 3.03 (m, 2H), 2.81 (m, 2H), 2.34 (m, 1H), 2.10 (m,1H), 1.83 (m, 4H).

The following compounds were prepared according to the general synthesisshown in scheme A6:

Ex SM Amine Characterisation 20 [AA- 25]

method: 4, RT: 4.14 min, MI: 352 [M + 1] 21 [AA- 26]

method: 2, RT: 2.32 min, MI: 340 [M + 1] 22 [AA- 26]

method: 2, RT: 2.73 min, MI: 354 [M + 1] 23 [AA- 26]

method: 2, RT: 2.66 min, MI: 354 [M + 1] 24 [AA- 27]

method: 2, RT: 2.36 min, MI: 354 [M + 1] 25 [AA- 27]

method: 2, RT: 2.68 min, MI 368 [M + 1] 26 [AA- 27]

method: 2, RT: 2.57 min, MI: 368 [M + 1] 27 [AA- 33]

method: 3, RT: 2.16 min, MI: 431 [M + 1] 28 [AA- 34]

method: 2, RT: 2.37 min, MI: 328 [M + 1] 29 [AA- 34]

method: 2, RT: 2.41 min, MI: 342 [M + 1] 30 [AA- 34]

method 2, RT: 2.51 min, MI: 342 [M + 1] 31 [AA- 35]

method: 2, RT: 2.30 min, MI: 328 [M + 1] 32 [AA- 35]

method 2, RT: 2.32 min, MI: 328 [M + 1] 33 [AA- 36]

method: 2, RT: 2.01 min, MI: 300 [M + 1] 34 [AA- 36]

method: 2, RT: 2.12 min, MI: 314 [M + 1] 35 [AA- 36]

method: 2, RT: 2.12 min, MI: 314 [M + 1] 36 [AA- 37]

method 2, RT: 1.92 min, MI: 300 [M + 1] 37 [AA- 37]

method: 2, RT: 2.08 min, MI: 314 [M + 1] 38 [AA- 37]

method: 2, RT: 2.52 min, MI: 314 [M + 1] 39 [AA- 38]

method: 2, RT: 1.60 min, MI: 329 [M + 1] 40 [AA- 39]

method: 2, RT: 2.07 min, MI: 314 [M + 1] 41 [AA- 39]

method 2, RT 2.16 min, MI: 328 [M + 1] 42 [AA- 29]

method: 3, RT: 1.48 min, MI: 384 [M + 1] 1H NMR (300 MHz, DMSO): 8.7 (d,2H) 8.42 (s, HCOOH, 1H) 8.26 (d, 2H), 3.94 (bs, 2H), 3.86 (bm, 4H), 3.86(bm, 2H), 3.30 (m, 2H), 3.22 (m, 4H), 43 [AA- 30]

method: 3, RT: 2.33 min, MI: 354 [M + 1] 44 [AA- 32]

method: 3, RT: 2.07 min, MI: 344 [M + 1] 45 [AA- 31]

method: 3, RT: 1.81 min, MI: 328 [M + 1]

General Synthesis of 5,6 Substituted4-amino-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-1] (Scheme A7)

Compounds were synthesised starting from an N-Boc protected amino acidderivative of general formula [F-14] which was converted to a primarycarboxamide derivative of general formula [F-15] by reaction withdi-tert-butyl dicarbonate in the presence of a base such as pyridine or2,6-lutidine and ammonium carbonate in an anhydrous solvent such asdioxane, THF or diethylether. The resultant primary carboxamidederivative was reduced to the amino derivative of general formula [F-16]with a borane reducing agent such as BH₃.THF or BH₃.SMe₂ in an anhydroussolvent such as THF, dioxane or diethylether. The resultant aminoderivative was then reacted with a5,6-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester [F-12] [preparedin scheme A5] in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC.

((S)-1-carbamoyl-2-p-tolyl-ethyl)-carbamic acid tert-butyl ester [AA-42]

To a stirred solution of(S)-2-tert-butoxycarbonylamino-3-p-tolyl-propionic acid (560 mg, 2mmol), pyridine (100 μl, 1.2 mmol) and di-tert-butyl dicarbonate (568mg, 2.6 mmol) in dry dioxane (4 ml) was added ammonium carbonate (240mg, 2.5 mmol). The mixture was stirred for 4 hours at room temperature.Ethylacetate was added and the mixture was washed with water and asolution of 5% H₂SO₄. The combined organic phases were dried withmagnesium sulfate, filtered and evaporated to provide the title compoundas a white solid. LCMS method: 2, RT: 3.69 min, MI: 279 [M+1].

[(S)-2-amino-1-(4-methyl-benzyl)-ethyl]-carbamic acid tert-butyl ester[AA-43]

A 1M solution of BH₃ in THF (15 ml, 15 mmol) was added dropwise to((S)-1-carbamoyl-2-p-tolyl-ethyl)-carbamic acid tert-butyl ester [AA-42](560 mg, 2 mmol), the solution was stirred overnight at room temperaturethen subsequently hydrolysed by slow addition of excess of 10% aceticacid/MeOH (30 ml) and stirred at room temperature for a further 2 hours.The solvent was removed under reduced pressure the residue dissolved inmethanol and passed through a SCX-2 cartridge and washed with methanol.The product was released from the cartridge using a solution of 2Mammonia/methanol. The solvent was evaporated to provide the titlecompound as a white solid. LCMS method: 2, RT: 2.42 min, MI: 265 [M+1].

[(S)-1-carbamoyl-2-(2-methoxy-phenyl)-ethyl]-carbamic acid tert-butylester [AA-44]

To a stirred solution of(S)-2-tert-butoxycarbonylamino-3-(2-methoxy-phenyl)-propionic acid (998mg, 3.3 mmol), pyridine (300 μl, 3.6 mmol) and di-tert-butyl dicarbonate(1.16 g, 5.32 mmol) in dry dioxane (10 ml) was added ammonium carbonate(512 mg, 5.32 mmol). The mixture was stirred for 4 hours at roomtemperature. Ethylacetate was added and after washings with water and asolution of 5% H₂SO₄. The combined organic phases were dried withmagnesium sulfate, filtered and evaporated to provide the title compoundas a white solid. LCMS method: 4, RT: 3.09 min, MI: 295 [M+1].

[(S)-2-amino-1-(2-methoxy-benzyl)-ethyl]-carbamic acid tert-butyl ester[AA-45]

A 1M solution of BH₃ in THF (15 ml, 15 mmol) was added dropwise to[(S)-1-carbamoyl-2-(2-methoxy-phenyl)-ethyl]-carbamic acid tert-butylester [AA-44] (980 mg, 3.32 mmol), the solution was stirred overnight atroom temperature then subsequently hydrolysed by slow addition of excessof 10% acetic acid/MeOH (30 ml) and stirred at room temperature for afurther 2 hours. The solvent was removed under reduced pressure theresidue dissolved in methanol and passed through a SCX-2 cartridge andwashed with methanol. The product was released from the cartridge usinga solution of 2M ammonia/methanol. The solvent was evaporated to providethe title compound as a white solid. LCMS method: 2, RT: 2.40 min, MI:281 [M+1].

(S)-1-(4-methyl-benzyl)-3-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propylamine[46]

To a solution of 2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester (100 mg, 0.182 mmol) [AA-25] in DMA (2 ml) was added[(S)-2-amino-1-(4-methyl-benzyl)-ethyl]-carbamic acid tert-butyl ester[AA-43] (58 mg, 0.218 mmol) followed by Et₃N (76 μl, 0.546 mmol), themixture was stirred at room temperature for 2 hours. Then the productwas extracted with DCM (2 ml) and washed with brine (3 ml). To theorganic phase was added TFA (2 ml) and the mixture was stirred at roomtemperature for 1 hour. After completion the mixture was loaded onto aSCX-2 cartridge and washed with methanol. The product was released fromthe cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method B) to yield tothe title compound. LCMS method: 4, RT: 4.85 min, MI: 430 [M+1]. 1H NMR(300 MHz, DMSO): 8.64 (d, 2H), 7.99 (d, 2H), 7.18 (m, 4H), 3.89 (m, 2H),3.49 (m, 2H), 2.98 (m, 1H), 2.94 (m, 2H), 2.78 (m, 2H), 2.31 (s, 3H),1.83 (m, 4H).

The following compounds were prepared according to the general synthesisshown in Scheme A7:

Ex SM Amino acid [F-14] Characterisation 47 [AA- 25]

method 3, RT: 2.47 min, MI: 446 [M + 1] 48 [AA- 25]

method; 3, RT: 2.64 min, MI: 430 [M + 1] 49 [AA- 25]

method: 3, RT: 2.66 min, MI: 446 [M + 1] 50 [AA- 25]

method: 3, RT: 2.76 min, MI: 434 [M + 1] 51 [AA- 25]

method 3, RT: 2.56 min, MI: 434 [M + 1] 52 [AA- 25]

method: 3, RT: 2.87 min, MI: 466 [M + 1] 53 [AA- 25]

method: 3, RT: 2.65 min, MI: 430 [M + 1] 54 [AA- 25]

method: 3, RT: 2.53 min, MI: 446 [M + 1] 55 [AA- 25]

method 3, RT: 2.23 min, MI: 432 [M + 1] 56 [AA- 25]

method: 3, RT: 1.87 min, MI: 417 [M + 1] 57 [AA- 25]

method: 3, RT: 1.98 min, MI: 417 [M + 1] 58 [AA- 25]

method: 3, RT: 2.18 min, MI: 417 [M + 1] 59 [AA- 25]

method: 3, RT: 2.26 min, MI: 423 [M + 1] 60 [AA- 25]

method: 3, RT: 2.44 min, MI: 396 [M + 1] 61 [AA- 25]

method: 3, RT: 2.59 min, MI: 472 [M + 1] 62 [AA- 25]

method: 3, RT: 2.21 min, MI: 380 [M + 1] 63 [AA- 25]

method: 4, RT: 4.60 min, MI: 455 [M + 1] 64 [AA- 32]

method: 4, RT: 4.55 min, MI: 464 [M + 1]

General Synthesis of (S)-3-(2 or3-hydroxy-phenyl)-N*1*-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propane-1,2-diamineDerivatives of General Formula [F-18] (Scheme A8)

Compounds were synthesised starting from (S)-3-(2 or3-methoxy-phenyl)-N*1*-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propane-1,2-diaminederivatives of general formula [F-17] (described in scheme A7) by ade-methylation reaction with a Lewis acid such as BBr₃ or AlCl₃ in achlorinated solvent such as DCM or DCE at low reaction temperature.After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the crude reactionproduct was purified by reverse phase preparative HPLC.

Synthesis of2-[(S)-2-amino-3-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-propyl]-phenol[65]

To a solution of(S)-3-(2-methoxy-phenyl)-N*1*-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propane-1,2-diamine[49] (30 mg, 0.06 mmol) in DCM (1 ml) at −30° C. was added dropwise asolution of 1 M BBr₃ in DCM (180 μl, 0.180 mmol) under a nitrogenatmosphere. The reaction mixture was stirred at −30° C. for 1 hour andthen stirred overnight at room temperature. The crude reaction mixturewas concentrated under reduced pressure and then purified by preparativeHPLC (method A) to yield to the title compound. LCMS method: 3, RT: 2.28min, MI: 432 [M+1].

The following compounds were prepared according to the general synthesisshown in Scheme A8:

Example SM Characterisation 66 [54] method: 3, RT: 2.34 min, MI: 432[M + 1]

General Synthesis of 5,6 Substituted4-amino-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-1] (Scheme A9)

Compounds were synthesised starting from the hydrochloride orhydrobromide salt of an α-amino acid carboxamide derivative of generalformula [F-19] which was converted to the free base by reaction with abase such as Et₃N or DIPEA in a chlorinated solvent such as DCM or DCE.The resultant free base was then reduced to a diamino derivative ofgeneral formula [F-20] by reaction with a borane reducing agent such asBH₃.THF or BH₃.SMe₂ in an anhydrous solvent such as THF, dioxane ordiethylether. The resultant diamino derivative [F-20] was then reactedwith a 5,6-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester of generalformula [F-12] [prepared in scheme A5] in a polar aprotic solvent suchas DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N,DIPEA or NMM at ambient temperature. After reaction work up, typicallyby a liquid-liquid extraction or purification by acidic ion exchangecatch-release the crude reaction product was purified by reverse phasepreparative HPLC.

Synthesis of (S)-3-phenyl-propane-1,2-diamine [AA-46]

To a suspension of (S)-2-amino-3-phenyl-propionamide hydrochloride (540mg, 2.7 mmol) in DCM (5 ml) was added Et₃N (3801, 2.7 mmol). Thesuspension was stirred for 2 h at room temperature, the resulting solidwas filtered and the filtrate was concentrated under reduced pressure toyield to a white solid to which was added dropwise a 1M solution of BH₃in THF (20 ml, 20 mmol) the solution was stirred overnight at reflux.After cooling the solution was hydrolysed by slow addition of excess of10% acetic acid/MeOH (30 ml) and refluxed for a further 2 hours. Thesolvent was removed under reduced pressure, the residue dissolved inmethanol and passed through a SCX-2 cartridge and washed with methanol.The product was released from the cartridge using a solution of 2Mammonia/methanol. The solvent was evaporated to provide the titlecompound as a white solid. LCMS method: 1, RT: 0.36 min, MI: 151 [M+1].

Synthesis of(S)—N*1*-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-butane-1,2-diamine[67]

To a solution of 2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-25] (100 mg, 0.180 mmol) in DMA (2 ml) was added(S)-3-phenyl-propane-1,2-diamine [AA-46] (30 mg, 0.180 mmol) followed byEt₃N (50 μl, 0.36 mmol), the mixture was stirred at room temperature for2 hours. After completion the mixture was loaded onto a SCX-2 cartridgeand washed with methanol. The product was released from the cartridgeusing a solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product was purifiedby preparative HPLC (method A) to yield to the title compound. LCMSmethod: 4, RT: 2.51 min, MI: 416 [M+1]. 1H NMR (300 MHz, DMSO): 8.64 (d,2H), 7.95 (d, 2H), 7.36 (m, 5H), 3.92 (m, 2H), 3.46 (m, 2H), 2.92 (m,1H), 2.91 (m, 2H), 2.79 (m, 2H), 1.83 (m, 4H).

The following compounds were prepared according to the general synthesisshown in Scheme A9:

SM Carboxamide Ex [F-12] [F-19] Characterisation 68 [AA-25]

method: 2, RT: 2.16 min, MI: 354 [M + 1] 1H NMR (300 MHz, DMSO): 8.7(d,2H), 8.2 (d, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.3 (m, 1H), 1.8 (m, 4H),1.6 (m, 2H), 1 (t, 3H) 69 [AA-26]

method: 2, RT: 2.94 min, MI: 430 [M + 1] 70 [AA-28]

method: 2, RT: 2.72 min, MI: 430 [M + 1] 71 [AA-25]

method: 3, RT: 2.54 min, MI: 416 [M + 1] 1H NMR (300 MHz, DMSO): 8.67(d, 2H), 7.9 (d, 2H), 7.3 (m, 5H), 3.9 (m, 2H), 3.53 (m, 2H), 2.92 (m,1H), 2.91 (m, 2H), 2.79 (m, 2H), 1.83 (m, 4H) 72 [AA-33]

method: 3, RT: 2.52 min, MI: 521 [M + 1] 73 [AA-33]

method: 3, RT: 2.53 min, MI: 521 [M + 1] 74 [AA-38]

method: 2, RT: 2.31 min, MI: 419 [M + 1] 75 [AA-39]

method: 2, RT: 2.56 min, MI: 404 [M + 1] 76 [AA-27]

method: 2, RT: 2.95 min, MI: 444 [M + 1] 77 [AA-30]

method: 3, RT: 2.77 min, MI: 444 [M + 1] 78 [AA-29]

method: 3, RT: 2.37 min, MI: 474 [M + 1] 79 [AA-29]

method: 3, RT: 2.37 min, MI: 474 [M + 1] 80 [AA-32]

method: 3, RT: 2.59 min, MI: 434 [M + 1] 81 [AA-32]

method: 3, RT: 2.60 min, MI: 434 [M + 1] 82 [AA-31]

method: 3, RT: 2.23 min, MI: 418 [M + 1] 83 [AA-31]

method: 3, RT: 2.27 min, MI: 418 [M + 1]

General Synthesis of 5,6 Substituted4-amino-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-1] (Scheme A10)

5,6-substituted 2-pyridin-4-yl-thieno [2,3-d]pyrimidin-4-ol derivativesof general formula [F-4] [prepared in scheme A2] were subjected to aactivation reaction by reaction with a solid supported sulfonyl chloridederivative such as benzenesulfonyl chloride on polystyrene resin in apolar aprotic solvent such as DMA, DMF, NMP in the presence of atertiary amine base such as Et₃N, DIPEA or NMM with a catalytic amountof DMAP at ambient temperature. Excess reagents and reactants wereremoved by filtration and washing the polystyrene resin with solventssuch as DCM, DMF, THF. The polymer supported reagent of general formula[F-21] was then reacted with an N-Boc protected diamino derivative ofgeneral formula [F-13] in a polar aprotic solvent such as DMA, DMF, NMPin the presence of a tertiary amine base such as Et₃N, DIPEA or NMM atambient temperature. The resin was filtered through a PTFE frit andwashed with a solvent such as DCM or ethylacetate, the filtrate wascombined and after reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC.

Synthesis of polystyrene supported benzenesulfonic acid2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ylester [AA-47]

2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ol[AA-8] (70 mg, 0.241 mmol) and PS-TSCl (70 mg, 0.241 mmol) were placedinto sealed filter cartridge. DMA was added (2 ml) followed by Et₃N (100μl, 0.723 mmol) and DMAP (1.5 mg, 0.001 mmol). The reaction mixture wasshaken for 3 hours at room temperature and then the resin was filtered,through a PTFE frit. The resin was washed with DCM to yield to thepolystyrene supported benzenesulfonic acid2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ylester [AA-77] which was used in the next step without furtherpurification.

Synthesis ofN*1*-(2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-yl)-ethane-1,2-diamine[84]

The polystyrene supported benzenesulfonic acid2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ylester [AA-47] (70 mg, 0.24 mmol) was placed in a filter cartridge andDMA (2 ml) was added followed by Boc-ethylenediamine (39 mg, 0.241 mmol)and Et₃N (67 μl, 0.482 mmol). The reaction was shaken overnight at roomtemperature. The resin was filtered through a PTFE frit and washed withethylacetate. The filtrate was concentrated under reduced pressure andthe crude product was dissolved in DCM (2 ml) and TFA (2 ml) was addedand the mixture was stirred at room temperature for 1 hour. Aftercompletion the mixture was loaded onto a SCX-2 cartridge and washed withmethanol. The product was released from the cartridge using a solutionof 2M ammonia/methanol. The ammonia/methanol eluent was concentratedunder reduced pressure and the crude product was purified by preparativeHPLC (method A) to yield to the title compound. LCMS method: 2, RT: 3.22min, MI: 340 [M+1].

The following compounds were prepared according to the general synthesisshown in Scheme A10:

Amine Ex SM [F-13] Characterisation 85 [AA-8]

method: 2, RT: 2.26 min, MI: 366 [M + 1] 1H NMR (300 MHz, DMSO): 8.72(d, 2H), 8.25 (d, 2H), 3.62 (m, 2H), 3.44 (m, 4H), 3.06 (m, 2H), 3.03(m, 4H), 1.88 (m, 2H), 1.64 (m, 4H) 86 [AA-8]

method: 2, RT: 2.27 min, MI: 380 [M + 1] 87 [AA-8]

method: 2, RT: 2.77 min, MI: 430 [M + 1] 88 [AA-8]

method: 2, RT: 2.25 min, MI: 354 [M + 1] 89 [AA-8]

method: 2, RT: 2.26 min, MI: 354 1H NMR (300 MHz, DMSO): 8.71 (d, 2H),8.26 [M + 1] (d, 2H), 3.83 (m, 1H), 3.75 (m, 1H), 3.62 (m, 1H), 3.09 (m,2H), 2.98 (m, 2H), 1.89 (m, 2H), 1.66 (m, 4H), 1.21 (d, 3H) 90 [AA-11]

method: 2, RT: 2.63 min, MI: 517 [M + 1] 91 [AA-22]

method: 2, RT: 2.41 min, MI: 362 [M + 1] 92 [AA-22]

method: 2, RT: 2.41 min, MI: 402 [M + 1] 93 [AA-23]

method: 2, RT: 2.48 min, MI: 467 [M + 1] 94 [AA-15]

method: 2, RT: 1.90 min, MI: 312 [M + 1] 95 [AA-15]

method: 2, RT: 1.91 min, MI: 326 [M + 1] 96 [AA-11]

method: 2, RT: 2.32 min, MI: 441 [M + 1]

General Synthesis of pyridyl Substituted4-amino-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-1] (Scheme A11)

A 2,4-dichloro-5,6,7,8-tetrahydro-enzo[4,5]thieno [2,3-d]pyrimidinederivative of general formula [F-21] was reacted with primary andsecondary amino derivative of general formula [F-13] in a polar aproticsolvent such as DMA, DMF, NMP in the presence of a tertiary amine basesuch as Et₃N, DIPEA or NMM at ambient temperature. Following reactionwork up, typically by a liquid-liquid extraction or purification byacidic ion exchange catch-release, the amino derivative of generalformula [F-23] was reacted with pyridyl boronic acids or boronate estersof general formula [F-24] in the presence of a palladium catalyst suchas Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂ a base such as Et₃N, KOH, Na₂CO₃ or NaOH ina polar solvent such as EtOH, THF, DMA or dioxane at high temperatureeither by heating thermally or using a microwave reactor. Followingreaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release the crude reactionproduct was purified by reverse phase preparative HPLC.

Synthesis of[2-(2-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [AA-49]

To a solution of2,4-dichloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[AA-48] (100 mg, 0.387 mmol) in DMA (5 ml) was added Boc-ethylenediamine(62 mg, 0.387 mmol) followed by Et₃N (110 μl, 0.774 mmol), the mixturewas stirred at room temperature for 2 hours. Then the product wasextracted with DCM (2×10 ml) and washed with brine (2×10 ml). Thecombined organic phases were dried with magnesium sulfate, filtered andevaporated to provide a brown solid. The residue was used withoutfurther purification in the next step. LCMS method: 1, RT: 6.26 min, MI:383 [M+1].

Synthesis ofN*1*-[2-(3-fluoro-pyridin-4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-ethane-1,2-diamine [97]

A microwave vial was charged with[2-(2-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [AA-49] (80 mg, 0.210 mmol),3-fluoropyridine-4-boronic acid hydrate (38 mg, 0.24 mmol), tetrakis(triphenyl phosphine) palladium (12 mg, 0.01 mmol), Na₂CO₃ (2M in water,300 μl, 0.6 mmol) and EtOH (1 ml). The reaction was heated to 150° C.for 15 minutes under microwave irradiation. The mixture was thenfiltered through a plug of silica, washed with methanol and the filtratewas concentrated under reduced pressure. To a solution of the crudeproduct in DCM (2 ml) was added TFA (2 ml) and the mixture was stirredat room temperature for 1 hour. After completion the mixture was loadedonto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method A) to yield tothe title compound. LCMS method: 2, RT: 2.41 min, MI: 344 [M+1].

The following compounds were prepared according to the general synthesisshown in Scheme A11:

Boronic acid Amine Ex SM [F24] [F-13] Characterisation  98 [AA-49]

method: 2, RT: 2.64 min, MI: 344 [M + 1]  99 [AA-49]

method: 2, RT: 2.56 min, MI: 358 [M + 1] 1H NMR (300 MHz, DMSO): 8.677(d, 1H), 8.26 (d, 1H), 8.34 (s, 1H), 3.83 (m, 1H), 3.75 (m, 1H), 3.62(m, 1H), 2.91 (m, 2H), 2.79 (m, 2H), 1.66 (m, 4H), 1.21 (d, 3H) 100[AA-49]

method: 2, RT: 2.52 min, MI: 358 [M + 1] 101 [AA-49]

method: 2, RT: 2.79 min, MI: 434 [M + 1] 1H NMR (300 MHz, DMSO): 8.64(d, 1H), 8.53 (d, 1H), 7.83 (m, 1H), 7.26 (m, 5H), 3.92 (m, 2H), 3.46(m, 2H), 2.92 (m, 1H), 2.91 (m, 2H), 2.79 (m, 2H), 1.83 (m, 4H) 102[AA-49]

method: 4, RT: 4.22 min, MI: 446 [M + 1]

Synthesis of4-[4-((S)-2-Amino-3-phenyl-propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-pyridin-3-ol[103] (Scheme A12)

To a solution of(S)—N*1*-[2-(3-methoxy-pyridin-4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine(prepared according to the general synthesis shown in scheme A11) [102](30 mg, 0.06 mmol) in DCM (1 ml) cooled to −30° C. was added dropwise asolution of 1 M BBr₃ in DCM (180 μl, 0.180 mmol) under nitrogen. Thereaction mixture was stirred at −30° C. for 1 hour and stirred overnightat room temperature. The residue was concentrated under reduced pressureand then dissolved in DMSO and purified by preparative HPLC (method B)to yield to the title compound. LCMS method: 4, RT: 4.43 min, MI: 432[M+1]. 1H NMR (300 MHz, DMSO): 8.30 (d, 1H), 8.10 (d, 1H), 7.81 d, 1H),7.28 (m, 5H), 3.46 (m, 2H), 3.40 (m, 1H), 2.96 (m, 2H), 2.79 (m, 4H),1.83 (m, 4H).

General Synthesis of1-[4-(2-amino-ethylamino)-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7-yl]-alkylanoneDerivatives of General Formula [[F-26] (Scheme A13)

4-benzenesulfonyloxy-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylicacid tert-butyl ester [AA-11] (described in scheme A2) was subjected toan activation by reaction with a solid supported sulfonyl chloridederivative such as benzenesulfonyl chloride on polystyrene in a polaraprotic solvent such as DMA, DMF, NMP in the presence of a tertiaryamine base such as Et₃N, DIPEA or NMM with a catalytic amount of DMAP atambient temperature. Excess reagents and reactants were removed byfiltration and washing the polystyrene resin with a solvent such as DCM,DMF, THF. The polymer supported reagent was then reacted with(2-amino-ethyl)-carbamic acid allyl ester in a polar aprotic solventsuch as DMA, DMF, NMP in the presence of a tertiary amine base such asEt₃N, DIPEA or NMM at ambient temperature. The resin was fitted througha PTFE frit and washed with a solvent such as DCM or ethylacetate, theextracts were combined and after reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release, the N-Boc derivative was deprotected under acidicconditions with a strong acid such as TFA, TCA, methanesulfonic acid,HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH to give[2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-50]. Reaction ofpyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-50] with an acyl chloride derivative of generalformula [F-27] in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM gave theN-acylated [F-25] derivative which was subjected to an N-allyldeprotection reaction with polymer supported palladium, polymersupported borohydride in DCM, MeOH and water to give the correspondingamino derivates [F-26]. Following reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release the crude reaction product was purified by reverse phasepreparative HPLC.

Synthesis of Polystyrene Supported4-benzenesulfonyloxy-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylicacid tert-butyl ester [AA-51]

2-pyridin-4-yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-ol[AA-11] (700 mg, 1.83 mmol) and PS-TSCl (1.2 g, 2.92 mmol) were placedinto filter cartridge closed with a stopper. DMA (10 ml) was addedfollowed by Et₃N (510 μl, 3.66 mmol) and DMAP (11 mg, 0.09 mmol). Thereaction was shaken for 3 hours at room temperature and then the resinwas filtered through a PTFE frit. The resin was washed with DCM (6 ml)to yield to the polystyrene supported4-benzenesulfonyloxy-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester [AA-51], which wasused in the next step without further purification.

Synthesis of[2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-50]

To the polystyrene supported4-benzenesulfonyloxy-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester [AA-51] placed intoa filter cartridge was added DMA (2 ml) followed byallyl-N-(2-aminoethyl)carbamate hydrochloride (397 mg, 2.2 mmol) andEt₃N (510 μl, 3.66 mmol). The reaction was shaken overnight at roomtemperature. The resin was filtered through a PTFE frit and washed withethylacetate (6 ml) followed by DCM (6 ml). The extracts were combinedand evaporated under reduced pressure. The crude reaction product wasdissolved in DCM (25 ml) and washed with sodium hydrogen carbonate (20ml) then brine (20 ml), dried with magnesium sulfate, filtered andevaporated under reduced pressure to provide an orange solid. To asolution of the crude product in DCM (5 ml) was added TFA (5 ml) and themixture was stirred at room temperature for 1 hour. After completion themixture was loaded onto a SCX-2 cartridge and washed with methanol. Theproduct was released from the cartridge using a solution of 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the crude product was used without furtherpurification in the next step. LCMS method: 1, RT: 4.23 min, MI: 411[M+1].

Synthesis of{2-[7-(2,2-dimethyl-propionyl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino]-ethyl}-carbamicacid allyl ester [AA-52]

To a solution of[2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-50] (50 mg, 0.121 mmol) in DMA (1 ml) at −10° C.were added trimethylacetyl chloride (16 μl, 0.133 mmol) andN,N,-di-isopropyethylamine (60 μl, 0.363 mmol). The mixture was stirredovernight. After completion the reaction mixture was treated with water(2 ml) and brine (2 ml) and extracted with DCM (3 ml). The organics wereevaporated under vacuum and the crude product was used without furtherpurification in the next step.

Synthesis of1-[4-(2-amino-ethylamino)-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-propan-1-one[104]

To a solution of{2-[7-(2,2-dimethyl-propionyl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino]-ethyl}-carbamicacid allyl ester [AA-52] (50 mg, 0.121 mmol) in DCM:MeOH:H₂O (5:4:1) (2ml) in a filter cartridge were added PS—PPh₃-Pd (18 mg, 0.002 mmol) andMP-BH₄ (116 mg, 0.363 mmol). The reaction was shaken for 2 h after thenthe solution was filtered through Na₂SO₄ plug. The filtrate wasconcentrated under reduced pressure and the crude residue was purifiedby preparative HPLC (method A) to yield to the title compound. LCMSmethod: 2, RT: 2.26 min, MI: 411 [M+1].

The following compounds were prepared according to the general synthesisshown in Scheme A13:

Acid chloride Ex SM [F-27] Characterisation 105 [AA-52]

method: 2, RT: 1.83 min, MI: 369 [M + 1] 106 [AA-52]

method: 2, RT: 1.97 min, MI: 383 [M + 1] 107 [AA-52]

method: 2, RT: 2.02 min, MI: 397 [M + 1] 108 [AA-52]

method: 2, RT: 2.01 min, MI: 395 [M + 1] 109 [AA-52]

method: 2, RT: 2.13 min, MI: 409 [M + 1] 110 [AA-52]

method: 2, RT: 2.32 min, MI: 411 [M + 1] 111 [AA-52]

method: 2, RT: 1.66 min, MI: 412 [M + 1]

General Synthesis ofN*1*-(7-alkyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2-diamine Derivatives of General Formula[F-28] (Scheme A14)

[2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-50] was reacted in reductive amination reactionwith aldehyde derivative of general formula [F-30] and a solid supportedborohydride reagent in acetic acid and a polar protic solvent such asMeOH or EtOH. The N-alkylated derivative of general formula [F-29] wassubjected to an N-allyl deprotection reaction with polymer supportedpalladium, polymer supported borohydride in DCM, MeOH and water toprovide the amino derivative [F-28]. Following reaction work up,typically filtration through a PTFE frit followed by a liquid-liquidextraction or purification by acidic ion exchange catch-release thecrude reaction product was purified by reverse phase preparative HPLC.

Synthesis of[2-(7-ethyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-53]

To a solution of[2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-50] (50 mg, 0.121 mmol) in MeOH (1 ml) in a filtercartridge were added MP-BH₄ (144 mg, 0.290 mmol) followed byacetaldehyde (4 μl, 0.075 mmol) and acetic acid (7 μl, 0.121 mmol). Thereaction was shaken overnight at room temperature and then filteredthrough a PTFE frit. The filtrate was evaporated under reduced pressureand the resulting residue was dissolved in methanol and the mixture wasloaded onto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure to yieldthe title compound which was used without further purification in thenext step.

Synthesis ofN*1*-(7-ethyl-2-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2-diamine[112]

To a solution of[2-(7-ethyl-2-pyridin-4-yl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid allyl ester [AA-53] (50 mg, 0.121 mmol) in DCM:MeOH:H₂O (5:4:1) (2ml) in a filter cartridge were added PS—PPh₃-Pd (18 mg, 0.002 mmol) andMP-BH₄ (116 mg, 0.363 mmol). The reaction was shaken for 2 h aftercompletion the solution was filtered through Na₂SO₄ plug. The filtratewas concentrated under reduced pressure and the residue purified bypreparative HPLC (method A) to yield to the title compound. LCMS method:2, RT: 1.89 min, MI: 355 [M+1].

The following compounds were prepared according to the general synthesisshown in Scheme A14:

Aldehyde Ex SM [F-30] Characterisation   113 [AA-50]

method: 2, RT: 1.96 min, MI: 341 [M + 1] 114 [AA-50]

method: 2, RT: 1.61 min, MI: 383 [M + 1]

General Synthesis of4-(4-alkyl-piperazin-1-yl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidineDerivatives of General Formula [F-31] (Scheme A15)

4-piperazin-1-yl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[3] was subjected to a reductive amination reaction with aldehydederivatives of general formula [F-30] and a solid supported borohydridereagent in acetic acid and a polar protic solvent such as MeOH or EtOHto yield the alkylated derivative [F-27]. Following reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release the crude reaction product was purified byreverse phase preparative HPLC.

Synthesis of4-(4-benzyl-piperazin-1-yl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[115]

To a solution of4-piperazin-1-yl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[3] (50 mg, 0.142 mmol) in MeOH (2 ml) in a filter cartridge were addedMP-BH₄ (170 mg, 0.341 mmol), p-anisaldehyde (11 μl, 0.09 mmol) andacetic acid (8 μl, 0.142 mmol). The reaction was shaken overnight atroom temperature and then filtered through a PTFE frit. The filtrate wasevaporated under reduced pressure and the resulting residue wasdissolved in methanol and the mixture was loaded onto a SCX-2 cartridgeand washed with methanol. The product was released from the cartridgeusing a solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and purified by preparative HPLC(method A) to yield to the title compound. LCMS method: 2, RT: 2.61 min,MI: 456 [M+1]. 1H NMR (300 MHz, DMSO): 8.70 (d, 2H), 8.22 (d, 2H), 7.21(d, 2H), 7.15 (d, 2H), 3.47 (m, 7H), 2.90 (m, 5H), 2.54 (s, 2H), 2.28(s, 3H), 1.87 (br s, 2H), 1.73 (br s, 2H).

The following compounds were prepared according to the general synthesisshown in Scheme A15:

Aldehyde Ex SM [F-30] Characterisation 116 [3]

method: 2, RT: 2.56 min, MI: 442 [M + 1] 117 [3]

method: 2, RT: 2.77 min, MI: 520 [M + 1] 118 [3]

method: 2, RT: 2.3 min, MI: 443 [M + 1] 119 [3]

method: 2, RT: 2.22 min, MI: 380 [M + 1] 120

method: 2, RT: 2.32 min, MI: 443 [M + 1] 121 [3]

method: 2, RT 2.97 min, MI: 510 [M + 1] 1H NMR (300 MHz, DMSO): 8.72 (d,2H), 8.24 (d, 2H), 8.17 (s, 1H), 7,73 (d, 2H), 7.58 (d, 2H), 3,66 (s,2H), 3.51 (m, 4H), 2.9 (m, 4H), 2.61 (m, 2H), 2.53 (m, 2H), 1.87 (m,2H), 1.74 (m, 2H) 122 [3]

method: 2, RT: 2.72 min, MI: 476 [M + 1] 123 [3]

method: 2, RT 2.78 min, MI: 476 [M + 1] 124 [3]

method: 2, RT: 2.76 min, MI: 476 [M + 1] 1H NMR (300 MHz, DMSO): 8.68(d, 2H), 8.22 (d, 2H), 8.16 (s, 1H), 7.34 (m, 4H), 3.45 (s, 2H), 3.48(m, 4H), 2.87 (m, 4H), 2.57 (m, 2H), 2.53 (m, 2H), 1.87 (m, 2H), 1.73(m, 2H) 125 [3]

method: 2, RT: 2.19 min, MI: 366 [M + 1] 1H NMR (300 MHz, DMSO): 8.68(d, 2H), 8.22 (d, 2H), 3.48 (m, 4H), 2.87 (m, 4H), 2.57 (m, 2H), 2.53(m, 2H), 2.28 (s, 3H), 1.87 (d, 2H), 1.72 (d, 2H) 126 [3]

method: 2, RT: 2.41 min, MI: 458 [M + 1] 127 [3]

method: 2, RT 2.83 min, MI: 520 [M + 1] 128 [3]

method: 2, RT: 2.57 min, MI: 520 [M + 1] 129 [3]

method: 2, RT: 2.32 min, MI: 408 [M + 1] 130 [3]

method: 2, RT: 2.23 min, MI: 443 [M + 1] 1H NMR (300 MHz, DMSO): 8.69(d, 2H), 8.53 (s, 1H), 8.48 (m, 1H), 8.23 (d, 2H), 7.75 (m, 1H), 7.35(m, 1H), 3.58 (m, 2H), 3.48 (m, 4H), 2.88 (m, 4H), 2.59 (m, 2H), 2.53(m, 4H), 1.87 (m, 2H), 1.73 (m, 2H) 131 [3]

method: 2, RT: 3.28 min, MI: 520 [M + 1] 132 [3]

method: 2, RT: 2.57 min, MI: 456 [M + 1] 133 [3]

method: 2, RT: 2.30 min, MI: 394 [M + 1] 134 [3]

method: 2, RT: 2.32 min, MI: 408 [M + 1]

General Synthesis of 5,6 Substituted4-alkoxy-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-32] (Scheme A16)

4-chloro-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[AA-24] was subjected to a nucleophilic substitution reaction with anamino alcohol or N-Boc protected amino alcohol of general formula [F-33]in the presence of a strong base such as NaH, KH or LDA in the presenceof an anhydrous polar aprotic solvent such as DMA, DMF or NNP. Afterreaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativewas deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction product was purified by reversephase preparative HPLC.

Synthesis ofdimethyl-[2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-ethyl]-amine[135]

To a mixture of4-chloro-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[AA-24] (80 mg, 0.280 mmol) and 2-dimethylaminoethanol (34 μl, 0.340mmol) in DMA (1 ml) was added NaH (13 mg, 0.560 mmol). The reactionmixture was allowed to stir at room temperature for 2 hours and aftercompletion the mixture was diluted with water and the product wasextracted into DCM (2×2 ml). The combined organic phases were dried withmagnesium sulfate, filtered and evaporated under reduced pressure andthe crude product was purified by preparative HPLC (method A) to yieldto the title compound. LCMS method: 2, RT: 2.20 min, MI: 355 [M+1]. 1HNMR (300 MHz, DMSO): 8.70 (d, 2H), 8.22 (d, 2H), 3.1 (m, 2H), 2.9 (m,2H), 2.75 (m, 2H), 2.65 (m, 2H), 2.34 (s, 6H), 1.83 (m, 4H).

Synthesis ofmethyl-[2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-ethyl]-amine[136]

To a mixture of4-chloro-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[AA-24] (80 mg, 0.280 mmol) and tert-butyl-N-2-hydroxyethylcarbamate (53μl, 0.340 mmol) in DMA (1 ml) was added NaH (13 mg, 0.560 mmol). Thereaction mixture was allowed to stir at room temperature for 2 hours andafter completion the mixture was diluted with water and the product wasextracted into DCM (2×2 ml). The combined organic phases were dried withmagnesium sulfate, filtered and evaporated under vacuum. To a solutionof the crude product in DCM (1 ml) was added TFA (1 ml) and the mixturewas stirred at room temperature for 1 hour. After completion the mixturewas loaded onto a SCX-2 cartridge and washed with methanol. The productwas released from the cartridge using a solution of 2M ammonia/methanol.The ammonia/methanol eluent was concentrated under reduced pressure andthe product was purified by preparative HPLC (method A) to yield to thetitle compound. LCMS method: 2, RT: 2.16 min, MI: 327 [M+1]. 1H NMR (300MHz, DMSO): 8.70 (d, 2H), 8.3 (d, 2H), 2.96 (m, 2H), 2.8 (m, 2H), 2.56m, 2H), 2.45 (m, 2H), 1.81 (m, 4H).

The following compounds were prepared according to the general synthesisshown in Scheme A16:

Alcohol Ex SM [F-33] Characterisation 137 [AA-24]

method: 2, RT: 2.83 min, MI: 341 [M + 1] 138 [AA-24]

method: 2, RT: 2.45 min, MI: 383 [M + 1] 139 [AA-24]

method: 2, RT: 2.20 min, MI: 353 [M + 1] 140 [AA-24]

method: 2, RT: 2.20 min, MI: 353 [M + 1] 141 [AA-24]

method: 2, RT: 2.29 min, MI: 367 [M + 1] 142 [AA-24]

method: 2, RT: 2.60 min, MI: 417 [M + 1] 143 [AA-24]

method: 2, RT: 2.56 min, MI: 417 [M + 1] 144 [AA-24]

method: 2, RT: 2.22 min, MI: 341 [M + 1] 145 [AA-24]

method: 2, RT: 2.88 min, MI: 341 [M + 1] 146 [AA-24]

method: 2, RT: 2.52 min, MI: 383 [M + 1] 147 [AA-24]

method: 2, RT: 3.47 min, MI: 403 [M + 1] 148 [AA-24]

method: 2, RT: 2.37 min, MI: 369 [M + 1] 149 [AA-24]

method: 2, RT: 2.31 min, MI: 355 [M + 1] 150 [AA-24]

method: 2, RT: 2.32 min, MI: 355 [M + 1] 151 [AA-24]

method: 2, RT: 2.40 min, MI: 369 [M + 1] 152 [AA-24]

method: 2, RT: 2.21 min, MI: 339 [M + 1] 153 [AA-24]

method: 2, RT: 2.27 min, MI: 367 [M + 1] 154 [AA-24]

method: 2, RT: 2.27 min, MI: 367 [M + 1] 155 [AA-24]

method: 2, RT: 2.49 min, MI: 403 [M + 1]

General Synthesis of 5,6 substituted4-alkoxy-2-pyridin-4-yl-thieno[2,3-d]pyrimidines [F-32] (Scheme A17)

2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-25] was subjected to a nucleophilic substitution reaction witha N-Boc protected amino alcohol of general formula F-33] in the presenceof a strong base such as NaH, KH or LDA in the presence of an anhydrouspolar aprotic solvent such as DMA, DMF or NNP. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the N-Boc derivative was deprotected underacidic conditions with a strong acid such as TFA, TCA, methanesulfonicacid, HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or and thecrude reaction product was purified by reverse phase preparative HPLC.

Synthesisof(S)-1-cyclohexyl-2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-ethylamine[156]

To a mixture of 2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-25] (100 mg, 0.185 mmol) and N-Boc-L-cyclohexylglycinol (67mg, 0.278 mmol) in DMA (1 ml) was added NaH (13 mg, 0.560 mmol). Thereaction mixture was allowed to stir at room temperature for 2 hours andafter completion the mixture was diluted with water and the product wasextracted into DCM (2×2 ml). The combined organic phases were dried withmagnesium sulfate, filtered and evaporated under reduced pressure. Thecrude product was dissolved in DCM (1 ml) and TFA (1 ml) was added andthe mixture was stirred at room temperature for 1 hour. After completionthe mixture was loaded onto a SCX-2 cartridge and washed with methanol.The product was released from the cartridge using a solution of 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the product was purified by preparative HPLC(method A) to yield to the title compound. LCMS method: 2, RT: 2.62 min,MI: 409 [M+1]. 1H NMR (300 MHz, DMSO): 8.7 (d, 2H), 8.3 (d, 2H), 4.7 (m,2H), 4.5 (m, 2H), 3 (m, 2H), 2.9 (m, 2H), 1.81 (m, 4H), 1.7 (m, 3H), 1.6(m, 3H), 1.2 (m, 4H).

The following compounds were prepared according to the general synthesisshown in Scheme A17:

Alcohol Ex SM [F-33] Characterisation 157 [AA-25]

method: 2, RT: 2.82 min, MI: 423 [M + 1] 1H NMR (300 MHz, DMSO): 8.7 (d,2H), 8.3 (d, 2H), 4.7 (m, 2H), 4.5 (m, 2H), 3.2 (m, 2H), 2.8 (m, 2H),1.81 (m, 4H), 1.7 (m, 4H), 1.6 (m, 2H), 1.4 (m, 2H), 1.2 (m, 2H), 0.9(m, 2H) 158 [AA-25]

method: 2, RT: 2.82 min, MI: 456 [M + 1]

General Synthesis of 5,6 substituted4-alkoxy-2-pyridin-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-32] (Scheme A18)

Compounds were synthesised starting from an N-Boc protected amino acidof general formula [F-34] which was converted to a primary alcoholderivative of general formula [F-35] by reduction with a borane reducingagent such as BH₃.THF or BH₃.SMe₂ in an anhydrous solvent such as THF,dioxane or diethylether. The resultant aminoalcohol derivative [F-35]was then reacted with a5,6-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl ester [AA-25] [preparedin scheme A5] in the presence of a strong base such as NaH, KH or LDA inthe presence of an anhydrous polar aprotic solvent such as DMA, DMF orNNP. After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativewas deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH the crude reaction product was purified by reversephase preparative HPLC.

Synthesis of [(S)-2-hydroxy-1-(4-methoxy-benzyl)-ethyl]-carbamic acidtert-butyl ester [AA-54]

A 1M solution of BH₃ in THF (1.7 ml, 1.7 mmol) was added dropwise to astirred solution of(S)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid (200mg, 0.678 mmol) in dry THF (2.5 ml) at 0° C. The mixture was stirred for2 hours at O° C. then hydrolysed by slow addition of excess of 10%acetic acid/MeOH (5 ml) and stirred at room temperature for a further 2hours. The solvent was removed under reduced pressure the residue wasdissolved in ethylacetate (5 ml) and washed with saturated sodiumbicarbonate (2×5 ml) and brine (2×5 ml). The combined organic phaseswere dried with magnesium sulfate, filtered and evaporated under reducedpressure to provide the title compound as a white solid which was usedwithout further purification in the next step. LCMS method: 1, RT: 2.82min, MI: 441 [M+1].

Synthesis of(S)-1-(4-methoxy-benzyl)-2-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-ethylamine [159]

To a solution of 2,4,6-triisopropyl-benzenesulfonic acid2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylester [AA-25] (50 mg, 0.091 mmol) in DMA (1 ml) was added[(S)-2-amino-1-(4-methyl-benzyl)-ethyl]-carbamic acid tert-butyl ester[AA-54] (31 mg, 0.110 mmol) followed by NaH (4 mg, 0.110 mmol), themixture was stirred at room temperature for 2 hours. After completionthe product was extracted with DCM (2 ml) and washed with brine (3 ml).To the organic phase was added TFA (2 ml) and the mixture was stirred atroom temperature for 1 hour. After completion the mixture was loadedonto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method A) to yield tothe title compound. LCMS method: 2, RT: 2.61 min, MI: 447 [M+1]. 1H NMR(300 MHz, DMSO): 8.7 (d, 2H), 8.1 (d, 2H), 7.2 (d, 2H), 6.9 (d, 2H), 4.7(m, 1H), 4.5 (m, 1H), 3.8 (s, 3H), 3.6 (m, 2H), 2.9 (m, 1H), 2.8 (m,2H), 2.7 (m, 2H), 1.81 (m, 4H).

The following compounds were prepared according to the general synthesisshown in Scheme A18:

Amino acid Ex SM [F-34] Characterisation 160 [AA-25]

method: 2, RT: 2.77 min, MI: 467 [M + 1] 161 [AA-25]

method: 2, RT: 2.81 min, MI: 467 [M + 1] 162 [AA-25]

method: 2, RT: 2.62 min, MI: 435 [M + 1] 163 [AA-25]

method: 2, RT: 2.69 min, MI: 435 [M + 1] 164 [AA-25]

method: 2, RT: 2.70 min, MI: 435 [M + 1] 165 [AA-25]

method: 2, RT: 2.70 min, MI: 435 [M + 1] 166 [AA-25]

method: 2, RT: 2.71 min, MI: 431 [M + 1] 167 [AA-25]

method: 2, RT: 2.74 min, MI: 431 [M + 1] 168 [AA-25]

method: 2, RT: 2.71 min, MI: 423 [M + 1] 169 [AA-25]

method: 2, RT: 2.71 min, MI: 447 [M + 1] 170 [AA-25]

method: 2, RT: 2.58 min, MI: 423 [M + 1] 171 [AA-25]

method: 2, RT: 2.76 min, MI: 495 [M + 1] 172 [AA-25]

method: 2, RT: 3.04 min, MI: 467 [M + 1] 173 [AA-25]

method: 2, RT: 2.81 min, MI: 467 [M + 1] 174 [AA-25]

method: 2, RT: 2.76 min, MI: 431 [M + 1] 175 [AA-25]

method: 2, RT: 2.19 min, MI: 407 [M + 1] 176 [AA-25]

method: 2, RT: 2.87 min, MI: 473 [M + 1] 177 [AA-25]

method: 2, RT: 2.82 min, MI: 473 [M + 1] 178 [AA-25]

method: 2, RT: 2.37 min, MI: 381 [M + 1] 179 [AA-25]

method: 2, RT: 2.38 min, MI: 381 [M + 1] 180 [AA-25]

method: 2, RT: 2.59 min, MI: 447 [M + 1]

General Synthesis of Substituted4-amino-2-pyrazolyl-4-yl-thieno[2,3-d]pyrimidine Derivatives of GeneralFormula [F-35] (Scheme A19)

A 2,4-dichloro-5,6,7,8-tetrahydro-enzo[4,5]thieno [2,3-d]pyrimidine ofgeneral formula [F-21] was reacted with primary and secondary aminoderivative of general formula [F-13] in a polar aprotic solvent such asDMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N,DIPEA or NMM at ambient temperature. Following reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the amino derivative of general formula [F-23]were reacted with pyrazolyl boronic acids or boronate esters of generalformula [F-36] in the presence of a palladium catalyst such as Pd(PPh₃)₄or Pd(PPh₃)₂Cl₂ a base such as Et₃N, KOH, Na₂CO₃ or NaOH in a polarsolvent such as EtOH, THF, DMA or dioxane at high temperature either byheating thermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the N-Boc derivative was deprotected underacidic conditions with a strong acid such as TFA, TCA, methanesulfonicacid, HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH thecrude reaction product was purified by reverse phase preparative HPLC.

Synthesis of[2-(2-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [AA-49]

To a solution of2,4-dichloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine[AA-48] (100 mg, 0.387 mmol) in DMA (5 ml) was added Boc-ethylenediamine(62 mg, 0.387 mmol) followed by Et₃N (110 μl, 0.774 mmol), the mixturewas stirred at room temperature for 2 hours. Then the product wasextracted with DCM (2×10 ml) and washed with brine (2×10 ml). Thecombined organic phases were dried with magnesium sulfate, filtered andevaporated under reduced pressure to provide a brown solid. The residuewas used without further purification in the next step. LCMS method: 1,RT: 6.26 min, MI: 383 [M+1].

Synthesis ofN*1*-[2-(1H-Pyrazol-4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-ethane-1,2-diamine[181]

A microwave vial was charged with[2-(2-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [AA-49] (40 mg, 0.17 mmol), 1H-pyrazole-4-boronicacid (23 mg, 0.20 mmol), tetrakis (triphenyl phosphine) palladium (10mg, 0.008 mmol), Na₂CO₃ (2M in water, 180 μl, 0.6 mmol) and EtOH (1 ml).The reaction was heated to 150° C. for 15 minutes under microwaveirradiation. The mixture was then filtered through a plug of silica,washed with methanol and the filtrate was concentrated under reducedpressure. To a solution of the crude product in DCM (2 ml) was added TFA(2 ml) and the mixture was stirred at room temperature for 1 hour. Aftercompletion the mixture was loaded onto a SCX-2 cartridge and washed withmethanol. The product was released from the cartridge using a solutionof 2M ammonia/methanol. The ammonia/methanol eluent was concentratedunder reduced pressure and the crude product was purified by preparativeHPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.20min, MI: 315 [M+1], 1H NMR (300 MHz, DMSO): 8.41 (s, 1H), 8.20 (s, 2H),6.80 (t, 1H), 3.74 (m, 2H), 3.06 (m, 2H), 2.94 (m, 2H), 2.74 (s, 2H),2.53 (s, 2H), 1.81 (s, 4H).

The following compounds were prepared according to the general synthesisshown in Scheme A19:

Boronic acid Amine Ex SM [F36] [F-13] Characterisation 182 [AA- 48]

method: 2, RT: 2.32 min, MI: 343 [M + 1] 1H NMR (300 MHz, DMSO): 8.37(s, 1H), 6.87 (t, 1H), 3.73 (m, 2H), 3.15 (m, 2H), 3.03 (m, 2H), 2.97(s, 2H), 2.74 (s, 2H), 2.49 (s, 6H), 1.84 (s, 4H) 183 [AA- 48]

method: 2, RT: 2.52 min, MI: 405 [M + 1] 184 [AA- 48]

method: 2, RT: 2.65 min, MI: 433 [M + 1] 185 [AA- 48]

method: 2, RT: 2.30 min, MI: 341 [M + 1] 1H NMR (300 MHz, DMSO): 8.20(s, 2H), 3.51 (m, 4H), 3.19 (m, 4H), 2.88 (m, 4H), 1.87 (m, 2H), 1.78(m, 2H) 186 [AA- 48]

method: 2, RT: 2.31 min, MI: 355 [M + 1] 1H NMR (300 MHz, DMSO): 8.17(s, 2H), 3.87 (m, 2H), 3.74 (m, 2H), 3.38 (m, 2H), 3.11 (m, 2H), 2.84(m, 2H), 1.88 (m, 2H), 1.77 (m, 2H) 187 [AA- 48]

method: 2, RT: 2.21 min, MI: 329 [M + 1] 188 [AA- 49]

method: 2, RT: 2.26 min, MI: 329 [M + 1] 189 [AA- 48]

method: 2, RT: 2.27 min, MI: 341 [M + 1] 190 [AA- 48]

method: 2, RT: 2.49 min, MI: 369[M + 1] 1H NMR (300 MHz, DMSO): 8.97 (s,1H), 3.51 (m, 6H), 2.84 (m, 6H), 1.88 (m, 2H), 1.77 (m, 2H) 191 [AA- 48]

method: 2, RT: 2.48 min, MI: 383[M + 1] 192 [AA- 49]

method: 2, RT: 2.38 min, MI: 357[M + 1] 193 [AA- 48]

method: 2, RT: 2.37 min, MI: 357[M + 1] 194 [AA- 48]

method: 2, RT: 2.41 min, MI: 369[M + 1] 195 [AA- 48]

method: 2, RT: 2.27 min, MI: 329[M + 1] 196 [AA- 48]

method: 7, RT: 3.76 min, MI: 431[M + 1]

4PT32P Compounds

In one approach, compounds of formula [G-100] (where A=NH or N alkyl)are prepared by reacting a compound of formula [G-102] (where X is ahalogen such as chlorine or a sulfonate) with a compound of formula[G-103](where A is NH or NH₂ and Z on the terminal nitrogen is H, alkylor a suitable nitrogen protecting group, such as Boc, Alloc, Cbz orFmoc) in a suitable solvent such as DMF in the presence of a suitablebase such as triethylamine.

The reaction is suitably conducted at an elevated temperature forexample 40° C. Where Z is a suitable nitrogen protecting group, such asBoc, Alloc, Cbz or Fmoc, compounds of formula [G-100] are prepared by asuitable deprotection reaction. For example: where Z is a Boc protectinggroup reaction with an acid such as TFA in a suitable solvent such asDCM. The reaction is suitably conducted at ambient temperature. In oneapproach, compounds of formula [G-100] (where A=0) are prepared byreacting a compound of formula [G-102] (where X is a halogen such aschlorine or sulfonate) with a compound of formula [G-103] (where A is OHand Z on the terminal nitrogen is H, alkyl or a suitable nitrogenprotecting group, such as Boc, Alloc, Cbz or Fmoc) in a suitable solventsuch as DMA in the presence of a suitable base such as sodium hydride.The reaction is suitably conducted at ambient temperature. Where Z is asuitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc,compounds of formula [G-100] are prepared by a suitable deprotectionreaction. For example: where Z is a Boc protecting group reaction withan acid such as TFA in a suitable solvent such as DCM. The reaction issuitably conducted at ambient temperature.

In one approach, compounds of formula [G-102] (where X is a halogen suchas chlorine) are prepared by reacting a compound of formula [G-104] witha suitable halogenating agent such as phosphorous oxychloride. Thereaction is suitably conducted at elevated temperature such as 125° C.Compounds of formula [G-102] (where X is a sulfonate) are prepared byreacting a compound of formula [G-104] with a suitably substitutedsulfonyl chloride in a suitable solvent such as DMA in the presence of asuitable base such as triethylamine and a catalytic amount of DMAP. Thereaction is suitably conducted at ambient temperature.

In one approach, compounds of formula [G-104] are prepared by reacting acompound of formula [G-105] (where R_(x1) is an alkyl group such asmethyl or ethyl) with a compound of formula [G-106] in a suitablesolvent such as dioxane with a suitable base such aspotassium-tert-pentylate. The reaction is suitably conducted at ambienttemperature.

In another approach compounds of formula [G-104] are prepared byreacting a compound of [G-107] with a compound of formula [G-108] in asuitable solvent such as methanol with a suitable protic acid such ashydrogen chloride. The reaction is suitably conducted at elevatedtemperature. Full aromatisation to yield compounds of formula [G-104] isachieved by reaction with an oxidising agent such as2,3-dichloro-5,6-dicyanobenzoquinone in a suitable solvent such asdichloromethane. The reaction is suitably conducted at ambienttemperature.

In one approach, compounds of formula [G-103] (where A is OH) areprepared by reacting a compound of formula [G-109] (where Z on theterminal nitrogen is H, alkyl or a suitable nitrogen protecting group,such as Boc, Alloc, Cbz or Fmoc) with a reducing agent such asborane-THF complex in a suitable solvent such as THF. The reaction issuitably conducted at low temperature for example 0° C. In one approach,compounds of formula [G-103] (where A is NH₂) are prepared by reacting acompound of formula [G-110] (where Z on the terminal nitrogen is H,alkyl or a suitable nitrogen protecting group, such as Boc, Alloc, Cbzor Fmoc) with a reducing agent such as borane-THF complex in a suitablesolvent such as THF. The reaction is suitably conducted at lowtemperature for example 0° C. In one approach, compounds of formula[G-110] are prepared by reacting compounds of formula [G-109] with Bocanhydride in the presence of a suitable base such as pyridine, ammoniumcarbonate in a suitable solvent such as dioxane. The reaction issuitably conducted at ambient temperature.

An example of a method as described above is illustrated in thefollowing scheme.

General Synthesis of 6,7-substituted 2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol, of General Formula [G-104] (Scheme B1)

A 4,5-substituted-3-Amino-thiophene-2-carboxylic acid alkyl esterderivative, of general formula [G-105] (where Rx=alkyl such as methyl orethyl) was subjected to a cyclisation reaction with a 4-cyanopyridinederivative of general formula [G-106] in the presence of a hinderedalkoxide base such as potassium-tert-pentylate 1.7M in toluene orpotassium-tert-butoxide in a dry non-aprotic solvent such as dioxane orTHF at ambient temperature, to yield the 6,7-substituted2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol derivative of formula[G-104].

Synthesis of 6-methyl-2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol[BB-01]

To a solution of 4-cyanopyridine (552 mg, 5.3 mmol) in dry dioxane (10ml) was added 3-amino-5-methyl-thiophene-2-carboxylic acid methyl ester(1 g, 5.84 mmol) followed by potassium-tert-pentylate 1.7M in toluene(6.9 ml, 11.7 mmol). The reaction mixture was stirred at roomtemperature overnight. After completion the precipitate formed wasfiltered and washed with diethyl ether. The residue was used without anyfurther purification in the next step. LCMS method: 3, RT: 2.44 min, MI:244 [M+1]. 1H NMR (300 MHz, DMSO): 2.60 (s, 3H), 7.23 (d, 1H), 8.05 (m,2H), 8.76 (m, 2H).

The following compounds were prepared according to the general synthesisshown in scheme B1:

6,7-Dimethyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-02] wasprepared by reaction of 3-amino-4,5-dimethyl-thiophene-2-carboxylic acidmethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as a yellowsolid. LCMS method: 3, RT: 3.05 min, MI: 258 [M+1].

6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-03] wasprepared by reaction of 3-amino-5-tert-butyl-thiophene-2-carboxylic acidmethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in tolueneand dioxane at room temperature to give the title compound as anoff-white solid. LCMS method: 3, RT: 3.02 min, MI: 286 [M+1].

7-(4-bromo-phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-04]was prepared by reaction of3-amino-4-(4-bromo-phenyl)-thiophene-2-carboxylic acid methyl ester,4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and dioxane atroom temperature to give the title compound as a yellow solid. LCMSmethod: 3, RT: 4.11 min, MI: 384-386 [M+1].

7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-05] was preparedby reaction of 3-amino-4-methyl-thiophene-2-carboxylic acid methylester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene anddioxane at room temperature to give the title compound as a yellowsolid. LCMS method: 1, RT: 3.09 min, MI: 243 [M+1].

6-phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-06] was preparedby reaction of 3-amino-5-phenyl-thiophene-2-carboxylic acid methylester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene anddioxane at room temperature to give the title compound as an off-whitesolid. LCMS method: 1, RT: 3.46 min, MI: 306 [M+1].

6-(4-tert-butyl-phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-07] was prepared by reaction of3-amino-5-(4-tert-butyl-phenyl)-thiophene-2-carboxylic acid methylester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene anddioxane at room temperature to give the title compound as an off-whitesolid. LCMS method: 1, RT: 4.78 min, MI: 362 [M+1].

2-(2-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-08] wasprepared by reaction of methyl 3-amino-2-thiophene-carboxylate,2-Chloro-4-pyridinecarbonitrile, potassium-tert-pentylate 1.7M intoluene and THF at room temperature to give the title compound as a paleyellow solid. LCMS method: 8, RT: 3.32 min, MI: 264 [M+1].

9-Chloro-2-(2-chloro-pyridin-4-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-4-ol[BB-09] was prepared by reaction of3-Amino-4-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and THF atroom temperature to give the title compound as an off-white solid. LCMSmethod: 2, RT: 3.6 min, MI: 314 [M+1].

2-Pyridin-4-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ol [BB-10] wasprepared by reaction of ethyl3-aminothieno[2,3-b]pyridine-2-carboxylate, 4-cyanopyridine,potassium-tert-pentylate 1.7M in toluene and THF at room temperature togive the title compound as an of-white solid. LCMS method: 2, RT: 2.57min, MI: 281 [M+1].

7,9-Dimethyl-2-pyridin-4-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ol[BB-11] was prepared by reaction of ethyl3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate,4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and THF atroom temperature to give the title compound as an off-white solid. LCMSmethod: 2, RT: 3.07 min, MI: 309[M+1].

2-Pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-13] was prepared byreaction of methyl 3-amino-2-thiophene-carboxylate,4-pyridinecarbonitrile, potassium-tert-pentylate 1.7M in toluene and THFat room temperature to give the title compound as a pale yellow solid:LCMS method B: 1.98 min, 100%, 230.00 [M+H]

General Synthesis of 6,7-substituted 2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol, of General Formula [G-104] (Scheme B2)

An 4,5-substituted-3-amino-thiophene-2-carboxylic acid amide derivativeof general formula [G-107] was subjected to a cyclisation reaction withan isonicotinaldehyde derivative of general formula [G-108] in thepresence of 4M hydrogen chloride in dioxane in a suitable solvent suchas methanol. The reaction is suitably conducted at an elevatedtemperature for example 140° C. in a microwave reactor for 20 minutes.Full aromatisation is subsequently achieved with2,3-dichloro-5,6-dicyanobenzoquinone in a suitable solvent such asdichloromethane at ambient temperature, to yield the 6,7-substituted2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol, of general formula [G-104].

Synthesis of 2-(3-Fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol[BB-14]

A microwave vial was charged with 3-amino-thiophene-2-carboxylic acidamide (2 g, 14.07 mmol), 3-fluoroisonicotinaldehyde (0.85 ml, 8.52mmol), hydrogen chloride 4M in dioxane (0.7 ml, 2.81 mmol) and methanol(20 ml). The reaction mixture was heated to 140° C. for 20 minutes undermicrowave irradiation. After completion, the mixture was concentratedunder reduced pressure. To a solution of the crude product indichloromethane (20 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone(3.2 g, 14.07). The mixture was stirred at room temperature for 18hours. After completion, the precipitate formed was filtered and washedwith methanol. The residue was used without any further purification inthe next step. LCMS method: 5, RT: 3.39 min, MI: 248 [M+1]. NMR 1H(DMSO, 300 MHz): 13.03 (s, 1H), 8.80 (d, 1H), 8.62 (dd, 1H), 8.27 (d,1H), 7.80 (t, 1H), 7.52 (d, 1H).

The following compounds were prepared according to the general synthesisshown in scheme B2:

2-(2-Chloro-5-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-15]

A microwave vial was charged with 3-amino-thiophene-2-carboxylic acidamide (1.3 g, 9.3 mmol), 2-Chloro-5-fluoro-4-formylpyridine (Ig, 5.6mmol), concentrated hydrogen chloride (1 drop) and methanol (10 ml). Thereaction mixture was heated to 120° C. for 20 minutes under microwaveirradiation. After completion, the mixture was concentrated underreduced pressure. To a solution of the crude product in dichloromethane(20 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (2.3 g, 9.3mmol). The mixture was stirred at room temperature for 18 hours. Aftercompletion, the precipitate formed was filtered and washed withmethanol. The residue was used without any further purification in thenext step. LCMS method: 8, RT: 3.20 min, MI: 281-283 [M+1]. 1H NMR(DMSO, 300 MHz): 8.68 (1H, d), 8.27 (1H, d), 7.96 (1H, d), 7.51 (1H, d).

2-(2-Chloro-3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-15a]

A microwave vial was charged with 3-amino-thiophene-2-carboxylic acidamide (0.5 g, 3.5 mmol), 2-Chloro-3-fluoro-4-formylpyridine (0.75 g,2.12 mmol), 1.25 N hydrogen chloride (1 drop) and methanol (4 ml). Thereaction mixture was heated to 120° C. for 20 minutes under microwaveirradiation. After completion, the mixture was concentrated underreduced pressure. To a solution of the crude product in dichloromethane(5 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (800 mg, 3.5mmol). The mixture was stirred at room temperature for 18 hours. Aftercompletion, the precipitate formed was filtered and washed withmethanol. The residue was used without any further purification in thenext step. LCMS method: 8, RT: 3.21 min, MI: 281-283 [M+1]. 1H NMR(DMSO) 13.09 (1H, s, br), 8.46 (1H, d), 8.29 (1H, d), 7.83 (1H, t), 7.51(1H, d).

2-(3-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-15b]

A microwave vial was charged with 3-amino-thiophene-2-carboxylic acidamide (1 g, 7.03 mmol), 3-Chloro-pyridine-4-carbaldehyde (0.6 g, 4.24mmol), 2.5 N hydrogen chloride in ethanol (0.56 mL, 1.4 mmol) andethanol (10 ml). The reaction mixture was heated to 140° C. for 20minutes under microwave irradiation. After completion, the precipitateformed was filtered and washed with DCM then methanol. The residue waspurified by flash column chromatography (SiO2, MeOH:DCM elution) to fivethe title compound (0.52 g, 47% yield). LCMS method: 10, MI: 264 [M+1].

General Synthesis of 7-halosubstituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol of GeneralFormula [G-113] (Scheme B3a)

A 6-substituted 2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol derivativeof general formula [G-112] was brominated at the C7 position in thepresence of a halogenating agent such as Br₂, N-Bromosuccinimide,Phosphorus(V) oxybromide, and an acidic reagent such as acetic acid. Orchlorinated at the C7 position in the presence of a halogenating agentsuch as N-chlorosuccinimide and an acidic reagent such as acetic acid togive the corresponding 7-halosubstituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol derivative ofgeneral formula [G-113], Scheme B3a.

Synthesis of 7-bromo-6-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-16]

A solution of bromine (1.2 ml, 23.2 mmol) in chloroform (10 ml) wasadded to a stirring solution of6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-01] (2.84 g,11.6 mmol) in chloroform (15 ml) acetic acid (15 ml) at 0° C. Themixture was allowed to warm to room temperature and stirred over night.After completion the resulting solid was filtered and washed withchloroform and diethylether to yield the title compound as a yellowsolid. LCMS method: 4, RT: 2.14 min, MI: 322-324 [M+1]. 1H NMR (300 MHz,DMSO): 8.76 (m, 2H), 8.05 (m, 2H), 2.60 (s, 3H).

The following compounds were prepared according to the general synthesisshown in scheme B3a:

Synthesis of7-Bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-17]

Bromine (1.2 ml, 24.27 mmol) was added to a stirring solution of2-(3-Fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-14] (2.00 g,8.09 mmol) in acetic acid (20 ml) at ambient temperature. The mixturewas heated to 80° C. and stirred over night under reflux conditions.After completion, 10% sodium thiosulphate solution (5 ml) was added andthe resulting solid was filtered and washed with water and ethyl acetateto yield the title compound as a colourless solid. LCMS method: 6, RT:4.33 min, MI: 326-238 [M+1]. NMR 1H (DMSO, 300 MHz): 7.82 (dd, 1H), 8.47(s, 1H), 8.63 (d, 1H), 8.81 (s, 1H), 13.28 (bs, 1H).

Synthesis of 7-Chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-18]

To a stirred suspension of 2-Pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-13] (0.5 g, 2.18 mmol) in AcOH (10 ml) was added NCS (1.46 g, 10.9mmol) and the reaction heated to 80° C. After 18 hr further NCS (0.58 g,4.36 mmol) was added and the mixture was left to stir at 80° C. for afurther another 24 hr. The reaction mixture was cooled and evaporatedunder reduced pressure and the resulting residue suspended in H₂O andthe solid formed was collected by filtration, to give the title compound(0.4 g, 70% yield) which was used without further purification: LCMSmethod B: 4.16 min, 64%, 263.95 [M+H]

Synthesis of7-Bromo-6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-19]

A solution of bromine (60 μL, 1.17 mmol) in chloroform (1 ml) was addedto a stirring solution of6-tert-Butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-03] (0.33 g,1.17 mmol) in chloroform (4 ml) and acetic acid (5 ml) at 0° C. Themixture was allowed to warm to room temperature and stirred over night.After completion the resulting solid was filtered and washed withchloroform and diethylether to yield the title compound as a yellowsolid. LCMS method: 3, RT: 4.22 min, MI: 364-366 [M+1].

Synthesis of 7-Bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-20]

To a stirred suspension of 2-Pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-13] (20 g, 87.2 mmol) in AcOH (400 ml) was added Br₂ (20 ml). Themixture was left to stir 80° C. for 24 hr then an additional Br₂ (10 ml)was added and the mixture was left to stir 80° C. for a further 24hours. The reaction mixture was cooled and poured into H₂O-ice mixture,and the yellow precipitate was collected by filtration and washed withsaturated sodium metabisulfite, then H₂O followed by Et₂O, to give thetitle compound as a pale yellow solid (24.1 g, 90% yield). LCMS method:8, RT: 3.28 min, MI: 307-309 [M+1]. 1H NMR (DMSO) 8.99 (2H, d), 8.49(1H, s), 8.42 (2H, d).

General Synthesis of 6-halosubstituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol Derivative ofGeneral Formula [G-116] (Scheme B3b)

A 7-substituted 2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol derivativeof general formula [G-115] was brominated at the C6 position in thepresence of a halogenating agent such as Br₂, N-Bromosuccinimide,Phosphorus(V) oxybromide, and an acidic reagent such as acetic acid. Orchlorinated at the C6 position in the presence of a halogenating agentsuch as N-chlorosuccinimide and an acidic reagent such as acetic acid togive the corresponding 6-halosubstituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol derivative ofgeneral formula [G-116], Scheme B3b.

Synthesis of 6-Bromo-7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-21]

A solution of bromine (600 μL, 4.1 mmol) in chloroform (30 ml) was addedto a stirring solution of7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-05] (1 g, 10.030mmol) in chloroform (20 ml) acetic acid (15 ml) at 0° C. The mixture wasallowed to warm to room temperature and stirred over night. Aftercompletion the resulting solid was filtered and washed with chloroformand diethylether to yield the title compound as a yellow solid, whichwas used without further purification in the next step: LCMS method B,Purity: 98%, RT: 3.85 min, MI: 321-323.

General Synthesis of 4PT32P Derivatives of General Formula [G-100](Scheme B4)

4PT32P derivatives of general formula [G-100] were prepared by thereaction of a 6,7-substituted 2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol, of general formula [G-104] (described in schemeB1 & B2) with 2,4,6-triisopropylbenzenesulfonyl chloride in a polaraprotic solvent such as DMA, DMF, NMP with a tertiary alkylamine basesuch as Et₃N, DIPEA or NMM and a catalytic amount of DMAP. Theintermediate 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester, of generalformula [G-111] was isolated and then reacted with a primary orsecondary amino derivative, of general formula [G-117], in a polaraprotic solvent such as DMA, DMF, NMP in the presence of a tertiaryamine base such as Et₃N, DIPEA or NMM at ambient temperature [Method A].After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativeswere deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction product was purified by reversephase preparative HPLC. 4PT32P derivatives of general formula [G-100]were prepared by the reaction of a 6,7-substituted 2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol, of general formula [G-104] (described in schemeB1, B2 & B3) with 2,4,6-triisopropylbenzenesulfonyl chloride in a polaraprotic solvent such as DMA, DMF, NMP with a tertiary alkylamine basesuch as Et₃N, DIPEA or NMM and a catalytic amount of DMAP then usedcrude and reacted further with a primary or secondary amino derivative,of general formula [G-117], in a polar aprotic solvent such as DMA, DMF,NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMMat ambient temperature [Method B] without further purification. Afterreaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativeswere deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction product was purified by reversephase preparative HPLC. 4PT32P derivatives of general formula [G-100]were prepared by the reaction of a 6,7-substituted 2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol of general formula [G-104] with a chlorinationreagent such as phosphorus oxychloride to give compounds of generalformula [G-112] and then reacted with a primary or secondary aminoderivative, of general formula [G-117], in a polar aprotic solvent suchas DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N,DIPEA or NMM at ambient temperature [Method C]. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the N-Boc derivatives were deprotected underacidic conditions with a strong acid such as TFA, TCA, methanesulfonicacid, HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH andthe crude reaction product was purified by reverse phase preparativeHPLC.

Method A

Synthesis of 2,4,6-triisopropyl-benzenesulfonic acid7-bromo-6-methyl-2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-yl ester[BB-22]

To a solution of7-bromo-6-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-16](3.76 g, 11.6 mmol) in DCM (15 ml) was added2,4,6-triisopropylbenzenesulfonyl chloride (4.25 g, 23.2 mmol), Et₃N(2.2 ml, 23.2 mmol) and DMAP (27 mg, 0.22 mmol). The mixture was stirredfor one hour. After completion the mixture was diluted with water andthe product was extracted into DCM (2×10 ml). The combined organicphases were dried (MgSO₄), filtered and evaporated under reducedpressure to provide the title compound as a brown solid. The crude wasused without further purification in the next step. LCMS method: 3, RT:6.36 min, MI: 588-590 [M+1].

Synthesis of(S)—N*1*-(7-bromo-6-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[300]

To a solution of 2,4,6-triisopropyl-benzenesulfonic acid7-bromo-6-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester[BB-22] (2.5 g, 4.24 mmol) in DMA (5 ml) was added(S)-3-phenyl-propane-1,2-diamine [AA-46] (700 μl, 4.66 mmol) followed byEt₃N (1.1 ml, 8.48 mmol), the mixture was stirred at room temperaturefor 2 hours. After completion the mixture was loaded onto a SCX-2cartridge and washed with methanol. The product was released from thecartridge using a solution of 2M ammonia/methanol. The ammonia/methanoleluent was concentrated under reduced pressure and the crude product waspurified by preparative HPLC (method A) to yield to the title compound.LCMS method: 4, RT: 4.07 min, MI: 454-456 [M+1]. ¹H NMR (300 MHz, DMSO):8.69 (d, 2H), 8.06 (d, 2H), 7.32 (m, 5H), 3.86 (m, 1H), 3.37 (m, 2H),2.77 (m, 2H), 2.59 (s, 3H)

Synthesis of 2,4,6-Triisopropyl-benzenesulfonic acid6-phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-23]

To a solution of 6-Phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-06] (671 mg, 2.2 mmol) in DCM (5 ml) was added2,4,6-triisopropylbenzenesulfonyl chloride (710 mg, 2.64 mmol) wereadded Et₃N (920 μl, 6.6 mmol) and DMAP (14 mg, 0.11 mmol). The mixturewas stirred for one hour. After completion the mixture was diluted withwater and the product was extracted into DCM (2×2 ml). The combinedorganic phases were dried with magnesium sulfate, filtered andevaporated to provide 2,4,6-Triisopropyl-benzenesulfonic acid6-phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-16] as abrown solid. The crude was used without further purification in the nextstep. LCMS method: 3, RT: 6.12 min, MI: 572 [M+1].

Synthesis of6-phenyl-4-piperazin-1-yl-2-pyridin-4-yl-thieno[3,2-d]pyrimidine

To a solution of 2,4,6-triisopropylbenzenesulfonic acid6-phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-23] (60mg, 0.105 mmol) in DMA (1 ml) was added piperazine (10 mg, 0.115 mmol)followed by Et₃N (30 μl, 0.210 mmol), the mixture was stirred at roomtemperature for 2 hours. The crude reaction mixture was extracted withDCM (1 ml) and washed with brine (2 ml) and the extracts were loadedonto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method A) to yield tothe desired compound. LCMS method: 2, RT: 2.20 min, MI: 374 [M+1]. 1HNMR (300 MHz, DMSO): 8.73 (dd, 2H), 8.27 (dd, 2H), 8 (s, 1H), 7.91 (d,2H), 7.51 (m, 3H), 4.06 (m, 4H), 3.04 (m, 4H).

The following 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl esters of generalformula [G-111] were prepared:

Synthesis of 2,4,6-triisopropylbenzenesulfonic acid6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-24]

To a solution of 6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-03] (630 mg, 2.2 mmol) in DCM (5 ml) was added2,4,6-triisopropylbenzenesulfonyl chloride (710 mg, 2.64 mmol), Et₃N(920 μl, 6.6 mmol) and DMAP (14 mg, 0.110 mmol). The mixture was stirredfor one hour. After completion the mixture was diluted with water andthe product was extracted into DCM (2×2 ml). The combined organic phaseswere dried (MgSO₄), filtered and evaporated under reduced pressure toprovide the title compound as a brown solid. The crude was used withoutfurther purification in the next step. LCMS method: 3, RT: 6.25 min, MI:551 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid6,7-dimethyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-25]was prepared by reaction of6,7-dimethyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-02],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.33 min, MI: 524 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-26] wasprepared by reaction of7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-05],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.15 min, MI: 510 [M+1].

2,4,6-triisopropyl-benzenesulfonic acid7-(4-bromo-phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester[BB-27] was prepared by reaction of7-(4-bromo-phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-04],2,4,6-triisopropylbenzenesulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.69 min, MI: 650 [M+1].

Synthesis of 2,4,6-Triisopropyl-benzenesulfonic acid7-bromo-6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester[BB-29]

2,4,6-Triisopropyl-benzenesulfonic acid7-bromo-6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester[BB-28] was prepared by reaction of7-Bromo-6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-19],2,4,6-triisopropyl benzene sulfonyl chloride, Et₃N, DMAP and DCM at roomtemperature to give the desired compound as a brown solid. LCMS method:3, RT: 6.56 min, MI: 630-632 [M+1].

Synthesis of(S)—N*1*-(2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-butane-1,2-diamine[302]

To a solution of 2,4,6-triisopropyl-benzenesulfonic acid7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-26] (100mg, 0.196 mmol) in DMA (2 ml) was added (S)-3-phenyl-propane-1,2-diamine[AA-46] (32 mg, 0.216 mmol) followed by Et₃N (55 μl, 0.392 mmol), themixture was stirred at room temperature for 2 hours. After completionthe mixture was loaded onto a SCX-2 cartridge and washed with methanol.The product was released from the cartridge using a solution of 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the crude product was purified by preparative HPLC(method B) to yield to the title compound. LCMS method: 4, RT: 3.70 min,MI: 376 [M+1]. 1H NMR (300 MHz, DMSO): 8.68 (dd, 2H), 8.10 (dd, 2H),7.80 (s, 1H), 7.34 (m, 5H), 3.87 (m, 1H), 3.39 (m, 2H), 2.79 (m, 2H),2.41 (s, 3H).

(S)—N*1*-(7-bromo-6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-(2-methoxy-phenyl)-propane-1,2-diamine[303]

To a solution of 2,4,6-triisopropyl-benzenesulfonic acid7-bromo-6-tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester[BB-29] (173 mg, 0.275 mmol) in DMA (2 ml) was added[(S)-2-amino-1-(2-methoxy-benzyl)-ethyl]-carbamic acid tert-butyl ester[AA-45] (85 mg, 0.302 mmol) followed by Et₃N (120 μl, 0.825 mmol), themixture was stirred at room temperature for 2 hours. The crude reactionmixture was extracted with DCM (2 ml) and washed with brine (3 ml). Tothe organic phase was added TFA (2 ml) and the mixture was stirred atroom temperature for 1 hour. After completion the mixture was loadedonto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method A) to yield tothe title compound. LCMS method: 4, RT: 3.79 min, MI: 526-528 [M+1].

Method B

Synthesis of(S)—N*1*-[7-Bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine[304]

To a solution of7-Bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-17](2.0 g, 6.13 mmol) in DCM (40 ml) was added2,4,6-triisopropylbenzenesulfonyl chloride (2.2 g, 7.36 mmol),triethylamine (2.6 ml, 18.40 mmol) and DMAP (75 mg, 0.613 mmol). Thesolution was stirred at room temperature for 4 hours.((S)-2-Amino-1-benzyl-ethyl)-carbamic acid tert-butyl ester (1.84 g,7.36 mmol) was added and the mixture was stirred at room temperature for18 hours. The crude reaction mixture was extracted with DCM (150 ml),washed with brine (100 ml) the combined organic phases were dried(MgSO₄), filtered and evaporated under reduced pressure to provide acrude gum which was titrutated with ether to provide the N-Boc protectedintermediated as a pale white solid. The N-Boc protected intermediatewas taken up in a 4M solution of HCl/dioxane (10 ml) and the mixture wasstirred at room temperature overnight. After completion the mixture wasloaded onto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure followedby trituration in ether to yield the desired compound. LCMS method: 9,RT: 5.34 min, MI: 458-460 [M+1]. 1H NMR (MeOD, 300 MHz): 8.61 (d, 1H),8.52 (dd, 1H), 8.18 (s, 1H), 8.02 (m, 1H), 7.32 (m, 5H), 3.99 (m, 2H),3.77 (m, 1H), 3.06 (d, 2H).

Synthesis of(R)-3-[2-(2-Chloro-5-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-31]

To a stirred suspension of2-(2-Chloro-5-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-15](1.46 g, 5.18 mmol) and DMAP (63 mg, 0.518 mmol) in DCM (10 ml) wasadded triethylamine (1.6 ml, 11.4 mmol) followed by2,4,6-Triisopropylbenzenesulfonyl chloride (2.35 g, 7.77 mmol). Thereaction mixture was stirred at room temperature for 1 hr, during whichtime the solution became clear. The crude reaction mixture wasevaporated under reduced pressure, then the residue was dissolved in DMA(10 ml) and triethylamine (1.6 ml, 11.4 mmol) followed by(R)-(+)-1-Boc-3-aminopyrrolidine (450 μL, 7.77 mmol) added and themixture was left to stir at room temperature for 18 hr. The mixture waspartitioned between (DCM:H₂O) and organic phase separated and evaporatedunder reduced pressure to give a pale brown oil, which was purified bynormal phase chromatography (SiO2, ethyl acetate: cyclohexane elution)to give the title compound (1.71 g, 73% yield: LCMS method 3: 4.70 min,95%, 450.06 [M+H]; 1H NMR (MeOD) 8.40 (1H, d), 8.05 (1H, d), 8.03 (1H,d), 7.44 (1H, d), 4.80 (1H, m), 3.87-3.77 (1H, m), 3.59-3.42 (2H, m),3.40 (1H, dd), 3.36-3.26 (1H, m), 2.18-2.09 (1H, m), 1.46 (9H, s).

Synthesis of(R)-3-[2-(2-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester[BB-32]

To a stirred suspension of2-(2-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-08] (2.69 g,10.2 mmol) and DMAP (125 mg, 1 mmol) in DCM (30 ml) was addedtriethylamine (3.1 ml, 22.4 mmol) followed by2,4,6-Triisopropylbenzenesulfonyl chloride (4.6 g, 15.3 mmol). Thereaction mixture was stirred at room temperature for 1 hr. The crudereaction mixture was evaporated under reduced pressure, then the residuewas dissolved in DMA (30 ml) and triethylamine (3.1 ml, 22.4 mmol)followed by (R)-(+)-1-Boc-3-aminopyrrolidine (2.6 ml, 15.3 mmol) addedand the mixture was left to stir at room temperature for 18 hr. Thecrude reaction mixture was partitioned between (DCM:H₂O) and organicphase separated, dried (MgSO₄), filtered and evaporated under reducedpressure to give a pale brown oil, which was purified by normal phasechromatography (SiO₂, ethyl acetate: cyclohexane elution) to give thetitle compound (2.2 g, 50% yield: LCMS method 3: 4.81 min, 85%, 432.07[M+H]; ¹H NMR (DMSO) 8.54 (1H, dd), 8.29 (1H, d), 8.28 (1H, s), 8.21(1H, d), 7.51 (1H, d), 4.89-4.80 (1H, m), 3.79-3.67 (1H, m), 3.51-3.25(3H, m), 2.30-2.19 (1H, m), 2.07-2.01 (1H, m), 1.40 (9H, s).

{1-Benzyl-2-[7-bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl})-carbamicacid tert-butyl ester [BB-33] was prepared by reaction of7-Bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-17],DMAP, triethylamine, 2,4,6-Triisopropylbenzenesulfonyl chloride in DCM,followed by reaction with ((S)-1-Aminomethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester to give the title compound: LCMS method B, RT:4.78 min, MI: 558-560

[1-Benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34] was prepared by reaction of7-Bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-20], DMAP,triethylamine, 2,4,6-Triisopropylbenzenesulfonyl chloride in DCM,followed by reaction with ((S)-1-Aminomethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester to give the title compound: LCMS method 3: 4.39min, 95%, 542.04 [M+H]; ¹H NMR (DMSO) 8.70 (2H, d), 8.39 (1H, s), 8.20(2H, d), 7.29-7.22 (5H, m), 6.83 (1H, d), 4.09-4.06 (1H, m), 3.78-3.71(1H, m), 3.51 (1H, m), 2.82-2.78 (2H, m), 1.23 (7H, s), 0.88 (2H, s).

(R)-3-(6-Bromo-7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-35] was prepared by reaction of6-Bromo-7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-21],DMAP, triethylamine, 2,4,6-Triisopropylbenzenesulfonyl chloride in DCM,followed by reaction with (R)-(+)-1-Boc-3-aminopyrrolidine to give thetitle compound: LCMS method 3 RT: 4.77 min, MI: 490-492

(R)-3-[7-Bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-36] was prepared by reaction of67-Bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-17],DMAP, triethylamine, 2,4,6-Triisopropylbenzenesulfonyl chloride in DCM,followed by reaction with (R)-(+)-1-Boc-3-aminopyrrolidine to give thetitle compound: LCMS method 3 RT: 4.49 min, MI: 494-496

Method C

Synthesis of 7-Bromo-4-chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidine(BB-38) 7-Bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-20]

(12 g, 38.9 mmol) was suspended in phosphorus oxychloride (120 ml) andthe suspension heated to 110° C. After 1 hour the reaction mixture wasallowed to cool then phosphorus oxychloride removed under reducedpressure and the residue azeotroped with toluene. The pH was adjusted topH 8 by the cautious addition of 2M NaOH and the mixture was left tostir at room temperature for 18 hours and the pale brown solid wascollected by filtration, washed with water and dried under reducedpressure to give the title compound which was used in the next stepwithout further purification. LCMS method: 5, RT: 5.68 min, MI: 327[M+1]. 1H NMR (300 MHz, DMSO) 8.92 (2H, dd), 8.88 (1H, s), 8.50 (2H,dd).

Synthesis of(S)—N*1*-(7-Bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine[305]

To a solution of Bromo-4-chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidine[BB-38] (100 mg, 0.307 mmol) in DMA (2 ml) was addedS-(−)-1,2-diaminopropane dihydrochloride (50 mg, 0.308 mmol) followed byEt₃N (128 μl, 0.921 mmol), and the mixture stirred at room temperaturefor 18 hours. After completion the mixture was loaded onto a SCX-2cartridge and washed with methanol. The product was released from thecartridge using a solution of 2M ammonia/methanol. The ammonia/methanoleluent was concentrated under reduced pressure and the crude product waspurified by preparative HPLC (method A) to yield the title compound.LCMS method: 3, RT: 2.25 min, MI: 364-366 [M+1]. 1H NMR (300 MHz, DMSO):8.74 (2H, dd), 8.41 (1H, s), 8.38 (1H, s), 8.34 (dd, 2H), 3.72 (m, 2H),3.46 (m, 1H), 1.21 (s, 3H).

Synthesis of 7-chloro-4-chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidine(BB-39)

To a stirred solution of7-Chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-18] (0.2 g, 0.78mmol) in DMF (2 ml) was added POCl₃ (40 μL) and the RM stirred at 80° C.for 48 hours. The reaction mixture was cooled and poured into ice-waterand the dark brown solid was collected by filtration to give the titlecompound which was used without further purification: LCMS method B 5.29min, 281.89 [M+H].

Synthesis of(S)—N*1*-(7-Chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[306]

To a stirred suspension of7-chloro-4-chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidine [BB-39] (0.5 g,0.18 mmol) in DMA (1 ml) was added((S)-1-aminomethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (30mg, 0.19 mmol) and triethylamine (50 μL, 0.36 mmol). The mixture wasleft to stir at room temperature for 18 hr then the crude reactionmixture was loaded onto an SCX cartridge and washed with methanol. Theproduct was released from the cartridge using a solution of 2Mammonia/methanol. The filtrate was evaporated under reduced pressure andthe crude reaction product was purified by preparative HPLC (method B)to give the title compound. LCMS method 5: 33.06 min, 85%, 396.04 [M+H];¹H NMR (DMSO, 300 MHz): 9.00 (1H, s), 8.67 (2H, d), 8.33 (2H, s), 7.99(2H, d), 7.36 (5H, m), 3.96 (1H, d), 3.60 (1H, m), 3.53 (1H, m), 3.01(1H, dd), 2.84 (1H, dd), 2.49 (2H, m).

The following compounds were prepared according to the general synthesisshown in Scheme B3:

Amine Ex SM Method [G-117] Characterisation 307 [BB- 24] A

method: 2, RT: 2.11 min, MI: 342 [M + 1] 308 [BB- 24] A

method: 2, RT: 2.15 min, MI: 342 [M + 1] 309 [BB- 25] A

method: 3, RT: 1.91 min, MI: 300 [M + 1] 310 [BB- 27] A

method: 3, RT: 2.41 min, MI: 426 [M + 1] 311 [BB- 24] A

method: 2, RT: 2.03 min, MI: 328 [M + 1] 312 [BB- 26] A

method: 2, RT: 1.88 min, MI: 312 [M + 1] 313 [BB- 23] A

method: 2, RT: 2.15 min, MI: 348 [M + 1] 314 [BB- 13] B

method: 4, RT: 3.18 min, MI: 362 [M + 1] 315 [BB- 13] B

method: 10, RT: 1.57 min, MI: 406 [M + 1], 316 [BB- 13] B

method: 10, RT: 1.23 min, MI: 312 [M + 1], 317 [BB- 13] B

method: 10, RT: 1.10 min, MI: 298 [M + 1], 318 [BB- 13] B

method: 10, RT: 1.07 min, MI: 298 [M + 1], 319 [BB- 13] B

method: 10, RT: 0.99 min, MI: 314 [M + 1], 320 [BB- 13] B

method: 10, RT: 1.11 min, MI: 355 [M + 1], 321 [BB- 13] B

method: 10, RT: 1.16 min, MI: 316 [M + 1], 322 [BB- 15b] B

method: 10, RT: 1.31 min, MI: 332 [M + 1], 323 [BB- 15b] B

method: 10, RT: 1.87 min, MI: 396 [M + 1], 324 [BB- 24] A

method: 4, RT: 3.32 min, MI: 418 [M + 1] 325 [BB- 25] A

method: 3, RT: 2.30 min, MI: 390 [M + 1] 326 [BB- 27] A

method: 3, RT: 2.73 min, MI: 513 [M + 1] 327 [BB- 27] A

method: 3, RT: 2.72 min, MI: 513 [M + 1] 328 [BB- 22] A

method: 4, RT: 4.11 min, MI: 390-392 [M + 1] 1H NMR (300 MHz, DMSO):8.73 (d, 2H), 8.30 (d, 2H), 4.88 (m, 1H), 3.41 (m, 2H), 3.15 (m, 1H),3.06 (m, 2H), 2.6 (s, 3H), 2.24 (m, 1H), 1.97 (m, 1H) 329 [BB- 22] A

method: 4, RT: 4.43 min, MI: 454-456 [M + 1] 330 [BB- 22] A

method: 4, RT: 3.79 min, MI: 378-380 [M + 1] 331 [BB- 22] A

method: 4, RT: 3.78 min, MI: 378-380 [M + 1] 332 [BB- 22] A

method: 4, RT: 4.26 min, MI: 390-392 [M + 1] 333 [BB- 29] A

method: 3, RT: 4.18 min, MI: 406-408 [M + 1] 334 [BB- 29] A

method: 4, RT: 4.42 min, MI: 496-498 [M + 1] 335 [BB- 29] A

method: 4, RT: 4.94 min, MI: 496-498 [M + 1] 336 [BB- 20] B

method: 4, RT: 3.82 min, MI: 440-442 [M + 1] 1H NMR (DMSO, 300 MHz):8.70 (2H, dd), 8.36(1H, s), 8.11 (2H, dd), 7.25 (m, 5H), 3.79 (dd, 1H),3.30 (m, 1H), 2.70 (m, 2H), 2.50 (m, 2H) 337 [BB- 21] B

method: 4, RT: 4.49 min, MI: 454 [M + 1] 338 [BB- 20] C

method: 3, RT: 2.49 min, MI: 365.9 [M + 1] 339 [BB- 20] C

method: 4, RT: 4.87 min, MI: 379.98 [M + 1] 340 [BB- 21] B

method: 3, RT: 2.49 min, MI: 391.92 [M + 1] 341 [BB- 20] C

method: 4, RT: 4.99 min, MI: 392.01 [M + 1] 342 [BB- 20] C

method: 3, RT: 1.97 min, MI: 391.92 [M + 1] 343 [BB- 20] C

method: 3, RT: 2.16 min, MI: 392 [M + 1] 344 [BB- 20] C

method: 3, RT: 2.34 min, MI: 364-366 [M + 1] 345 [BB- 20] C

method: 3, RT: 2.28 min, MI: 364-366 [M + 1] 346 [BB- 20] C

method: 3, RT: 2.57 min, MI: 406-408 [M + 1] 347 [BB- 20] C

method: 3, RT: 2.39 min, MI: 392-394 [M + 1] 348 [BB- 20] C

method: 3, RT: 2.64 min, MI: 446-448 [M + 1] 349 [BB- 20] C

method: 3, RT: 1.78 min, MI: 350-352 [M + 1] 350 [BB- 20] C

method: 3, RT: 1.89 min, MI: 376-378 [M + 1] 351 [BB- 20] C

method: 8, RT: 1.88 min, MI: 376-378 [M + 1] 1H NMR (DMSO, 300 MHz):8.96 (2H, s, br), 8.83 (2H, d), 8.54 (1H, d), 8.48 (2H, dd), 8.45 (1H,s), 4.95 (1H, m), 3.70 (1H, m), 3.28 (3H, m), 2.35 (1H, m), 2.15 (1H, m)352 [BB- 17] B

method: 6, RT: 4.95 min, MI: 394-396 [M + 1] 1H NMR (DMSO, 300 MHz):8.69(1H, d), 8.57 (1H, dd), 8.50 (1H, s), 8.06 (1H, m), 4.80 (1H, m),3.87-3.77 (1H, m), 3.59-3.42 (2H, m), 3.40 (1H, dd), 3.36- 3.26 (1H, m),2.18-2.09 (1H, m) 353 [BB- 14] B

method: 5, RT: 2.02 min, MI: 304 [M + 1] 354 [BB- 14] B

method: 5, RT: 2.06 min, MI: 316 [M + 1] 1H NMR (DMSO, 300 MHz):8.70(1H, d), 8.56 (1H, dd), 8.40 (1H, s), 8.07 (1H, m), 7.52 (1H, d),4.78 (1H, m), 3.49 (1H, m), 3.32 (1H, m), 3.23 (2H, m), 2.26 (1H, m),2.09 (1H, m) 355 [BB- 14] B

method: 5, RT: 3.02 min, MI: 380 [M + 1] [BB- 39a] [BB- 20] C

method: 5, RT: 3.13 min, MI: 440-442 [M + 1] [BB- 39b] [BB- 15a] C

method: 8, RT: 4.70 min, MI: 448-450 [M + 1] 1H NMR (DMSO) 8.37 (1H, d),8.32 (1H, d), 8.23 (1H, d), 8.06 (1H, t), 7.50 (1H, d), 4.74- 4.69 (1H,m), 3.78-3.61 (1H, m), 3.49-3.41 (1H, m), 3.35- 3.25 (2H, m), 2.26-2.15(1H, m), 2.08-2.01 (1H, m).

General Synthesis of 6,7-substituted-4amino-2-pyridin-4-yl-thieno[3,2-d]pyrimidines

(Scheme B4)

6,7-substituted 2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol, of generalformula [G-104] (prepared in scheme B1) were subjected to a activationreaction by reaction with a solid supported sulfonyl chloride derivativesuch as benzene sulfonyl chloride on polystyrene in a polar aproticsolvent such as DMA, DMF, NMP in the presence of a tertiary amine basesuch as Et₃N, DIPEA or NMM with a catalytic amount of DMAP at ambienttemperature. Excess reagents and reactants were removed by filtrationand washing the polystyrene resin with solvents such as DCM, DMF, THF.The polymer supported reagent, of general formula [G-118], was thenreacted with a primary or secondary amino derivative, of general formula[G-117], in a polar aprotic solvent such as DMA, DMF or NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. The resin was filtered through a PTFE frit, washed with asolvent such as DCM and the filtrate and combined washings were loadedonto an acidic ion exchange catch release cartridge, which was washedwith an organic solvent such as methanol and then the product wasreleased with methanolic ammonia solution and the crude product waspurified by reverse phase preparative HPLC. The N-Boc derivatives weredeprotected under acidic conditions with a strong acid such as TFA, TCA,methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE, THF,EtOH or MeOH and the crude reaction mixture was purified by acidic ionexchange catch-release or reverse phase preparative HPLC.

Synthesis of Polystyrene Supported benzenesulfonic acid6-(4-tert-butyl-phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester[BB-40]

6-(4-tert-butyl-phenyl)-2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol[BB-07](60 mg, 0.167 mmol) and PS-TSCl (120 mg, 0.250 mmol) were placedinto filter cartridge closed with a stopper. DMA was added (2 ml)followed by Et₃N (70 μl, 0.5 mmol) and DMAP (1.1 mg, 0.009 mmol). Thereaction was shaken for 3 hours at room temperature and then the polymerwas filtered (after removing the stopper). The resin was washed with DCMto yield to the polystyrene supported benzenesulfonic acid6-(4-tert-butyl-phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylester.

Synthesis of6-(4-tert-butyl-phenyl)-4-[1,4]diazepan-1-yl-2-pyridin-4-yl-thieno[3,2-d]pyrimidine[356]

To the polystyrene supported benzenesulfonic acid6-(4-tert-butyl-phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester[BB-40] placed into a filter cartridge was added DMA (2 ml) followed byhomopiperazine (20 mg, 0.2 mmol) and Et₃N (70 μl, 0.5 mmol). Thereaction was shaken overnight at room temperature. The resin wasfiltered and washed with ethylacetate and the mixture was loaded onto aSCX-2 cartridge and washed with methanol. The product was released fromthe cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method A) to yield tothe title compound. LCMS method: 2, RT: 2.66 min, MI: 444 [M+1]. 1H NMR(300 MHz, DMSO): 8.68 (d, 2H), 8.22 (d, 2H), 7.82 (s, 1H), 7.8 (d, 2H),7.52 (d, 2H), 4.22 (m, 2H), 4.15 (m, 2H), 3.28 (m, 2H), 3.06 (m, 2H),2.13 (m, 2H), 1.32 (s, 9H).

The following compounds were prepared according to the general synthesisshown in Scheme B4:

Amine Ex SM [G-117] Characterisation 357 BB- 07

method: 2, RT: 2.67 min, MI: 430 [M + 1] 358 BB- 07

method: 2, RT: 2.73 min, MI: 418 [M + 1] 359 BB- 07

method: 2, RT: 2.67 min, MI: 418 [M + 1] 360 BB- 07

method: 2, RT: 2.65 min, MI: 404 [M + 1] 361 BB- 05

method: 2, RT: 1.81 min, MI: 300 [M + 1] 362 BB- 05

method: 2, RT: 1.88 min, MI: 326 [M + 1] 1H NMR (300 MHz, DMSO): 8.76(m, 2H), 8.33 (m, 2H), 7.94 (s, 1H), 4.22 (m, 1H), 4.09 (m, 3H), 3.74(m, 2H), 3.41 (m, 2H), 2.43 (s, 3H), 1.95 (m, 2H) 363 BB- 05

method: 2, RT: 1.82 min, MI: 312 [M + 1] 1H NMR (300 MHz, DMSO): 8.72(m, 2H), 8.35 (m, 2H), 8.16 (m, 1H), 7.93 (s, 1H), 4.02 (m, 4H), 2.96(m, 4H), 2.44 (s, 3H) 364 BB- 05

method: 2, RT: 1.79 min, MI: 312 [M + 1] 365 BB- 05

method: 2, RT: 1.89 min, MI: 300 [M + 1] 366 BB- 06

method: 2, RT: 2.22 min, MI: 362 [M + 1] 367 BB- 06

method: 2, RT: 2.21 min, MI: 362 [M + 1] 368 BB- 06

method: 2, RT: 2.23 min, MI: 388 [M + 1] 1H NMR (300 MHz, DMSO): 8.72(d, 2H), 8.27 (d, 2H), 7.97 (s, 1H), 7.90 (d, 2H), 7.49 (m, 3H), 4.21(m, 2H), 4.11 (m, 2H), 3.33 (m, 2H), 3.08 (m, 2H), 2.1 (m, 2H) 369 BB-05

method: 2, RT: 1.82 min, MI: 300 [M + 1] 370 BB- 05

method: 2, RT: 1.76 min, MI: 286[M + 1] 371 BB- 09

method: 2, RT: 2.24 min, MI: 387 [M + 1] 372 BB- 09

method: 2, RT: 2.57 min, MI: 446 [M + 1] 373 BB- 09

method: 2, RT: 2.22 min, MI: 370 [M + 1] 374 BB- 09

method: 2, RT: 2.26 min, MI: 370 [M + 1] 375 BB- 10

method: 2, RT: 1.82 min, MI: 323 [M + 1] 1H NMR (300 MHz, DMSO): 8.86(dd, 1H), 8.77 (m, 3H), 8.41 (m, 2H), 7.69 (dd, 1H), 3.86 (m, 2), 3.10(m, 2H) 376 BB- 10

method: 2, RT: 1.86 min, MI: 349 [M + 1] 377 BB- 10

method: 2, RT: 1.92 min, MI: 362 [M + 1] 1H NMR (300 MHz, DMSO): 8.97(dd, 1H), 8.76 (m, 3H), 8.34 (m, 2H), 7.65 (dd, 1H), 4.07 (m, 4), 3.18(m, 2H), 2.93 (m, 2H) 378 BB- 10

method: 2, RT: 1.9 min, MI: 337 [M + 1] 379 BB- 10

method: 2, RT: 1.89 min, MI: 337 1H NMR (300 MHz, DMSO): 8.87 (dd, 1H),8.79 (m, 3H), 8.44 (m, 2H), 7.69 (dd, 1H), 3.80 (m, 2), 3.48(m, 1H),1.26(d, 3H) 380 BB- 11

method: 2, RT: 2.15 min, MI: 377 381 BB- 11

method: 2, RT: 2.17 min, MI: 391 382 BB- 11

method: 2, RT: 2.19 min, MI: 365 383 BB- 11

method: 2, RT: 2.16 min, MI: 365 384 BB- 09

method: 2, RT: 2.32 min, MI: 382 385 BB- 09

method: 2, RT: 2.32 min, MI: 370 386 BB- 09

method: 2, RT: 2.16 min, MI: 356 387 BB- 09

method: 2, RT: 2.20 min, MI: 382 1H NMR (300 MHz, DMSO): 8.78 (dd, 2H),8.40 (dd, 2H), 8.18 (m, 1H), 7.69 (dd, 2H), 4.04 (m, 4), 2.98 (m, 4H)

General Synthesis of 6 or 7 aryl substituted-4PT32P Derivatives, ofGeneral Formula [G-120] and [G-122] (Scheme B5)

The 7-bromo-6-substituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidinederivative, of general formula [G-119] or the6-bromo-7-substituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidine derivative,of general formula [G-121] were reacted in a Suzuki type reactionutilising a suitable boronic acid or boronic ester, of general formula[G-123], a palladium catalyst such as Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂ a basesuch as Et₃N, KOH, Na₂CO₃ or NaOH in a polar solvent such as EtOH, THF,DMA or dioxane at high temperature either by heating thermally or usinga microwave reactor. After reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release, the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, TCA, methanesulfonic acid,HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH and thecrude reaction product was purified by reverse phase preparative HPLC.

Synthesis of(S)—N*1*-[6-methyl-7-(2H-pyrazol-3-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine[388]

A microwave vial was charged with(S)—N*1*-(7-bromo-6-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[300](50 mg, 0.100 mmol), 1H-pyrazole-5-boronic acid (13 mg, 0.115mmol), tetrakis (triphenyl phosphine) palladium (11 mg, 0.009 mmol),Na₂CO₃ (2M in water, 100 μl, 0.2 mmol) and EtOH (2 ml). The reaction washeated to 150° C. for 15 minutes under microwave irradiation. Themixture was then filtered through a plug of silica, washed with methanoland the filtrate was concentrated under reduced pressure. The crudereaction product was dissolved in DCM (2 ml) and TFA (2 ml) was addedand the mixture was stirred at room temperature for 1 hour. Aftercompletion the mixture was loaded onto a SCX-2 cartridge and washed withmethanol. The product was released from the cartridge using a solutionof 2M ammonia/methanol. The ammonia/methanol eluent was concentratedunder reduced pressure and the crude product was purified by preparativeHPLC (method B) to yield to the title compound. LCMS method: 4, RT: 3.71min, MI: 442 [M+1]. 1H NMR (DMSO, 300 MHz): 8.67 (d, 2H), 8.06 (d, 2H),8.30 (d, 1H), 7.88 (d, 1H), 7.33 (m, 5H), 3.88 (m, 1H), 3.41 (m, 2H),2.93 (m, 2H), 2.83 (s, 3H).

Synthesis of[7-Methyl-6-(2H-pyrazol-3-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[389]

A microwave vial was charged with(R)-3-(6-Bromo-7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-35] (100 mg, 0.200 mmol),1H-pyrazole-5-boronic acid (26 mg, 0.23 mmol), tetrakis (triphenylphosphine) palladium (31 mg, 0.02 mmol), Na₂CO₃ (2M in water, 200 μl,0.4 mmol) and EtOH (2 ml). The reaction was heated to 150° C. for 15minutes under microwave irradiation. The mixture was then filteredthrough a plug of silica, washed with methanol and the filtrate wasconcentrated under reduced pressure. The crude reaction product wasdissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture wasstirred at room temperature for 1 hour. After completion the mixture wasloaded onto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method B) to yield tothe title compound. LCMS method: 2, RT: 2.43 min, MI: 378. 1H NMR (DMSO,300 MHz): 8.28 (dd, 1H), 8.73 (dd, 2H), 8.35 (dd, 2H), 7.95 (d, 1H),4.93 (m, 1H), 3.48 (m, 1H), 3.25 (m, 1H), 3.17 m, 1H), 3.14 (m, 1H),2.61 (s, 3H), 2.28 (M, 1H), 2.05 (m, 1H).

The following compounds were prepared according to the general synthesisshown in Scheme B5:

Boronic acid^(a) Example SM [G-123] Characterisation 390 [336]

method: 4, RT: 3.26 min, MI: 428 [M + 1] 1H NMR (DMSO, 300 MHz) 8.72(2H, d), 8.56 (1H, s, br), 8.43 (3H, m, br), 8.12 (2H, dd), 7.78 (1H, d,br), 7.34 (5H, m), 3.91 (1H, m), 3.45 (2H, m), 2.82 (2H, m) 391 [336]

method: 4, RT: 3.30 min, MI 442 [M + 1] 392 [336]

method: 4, RT: 3.65 min, MI 457 [M + 1] 1H NMR (DMSO, 300 MHz): 8.66(2H, d), 8.38 (1H, s, br), 8.22 (1H, s), 8.00 (2H, d), 7.30 (6H, m),3.85 (1H, m, br), 3.34 (2H, m), 2.73 (2H, t), 2.43 (3H, s), 2.25 (3H,s). 393 [336]

method: 3, RT: 2.25 min, MI: 428 [M + 1] 394 [336]

method: 3, RT: 2.81 min, MI: 484 [M + 1] 395 [336]

method: 3, RT: 2.92 min, MI: 458 [M + 1] 1H NMR (DMSO, 300 MHz): 8.72(2H, dd), 8.50 (1H, s, br), 8.39 (1H, s), 8.29 (1H, s), 8.12 (2H, dd),7.72 (1H, s), 7.35 (4H, m), 7.20 (1H, s), 3.91 (1H, d), 3.48 (1H, d),2.84 (1H, m), 2.49 (2H, m), 2.29 (3H, s) 396 [336]

method: 3, RT: 2.89 min, MI: 458 [M + 1] 1H NMR (DMSO, 300 MHz): 8.68(2H, dd), 8.61 (1H, s, br), 8.30 (1H, s), 8.25 (1H, s), 8.06 (2H, dd),7.57 (1H, d), 7.35 (4H, m), 7.06 (1H, d), 3.95 (1H, d), 3.52 (1H, m),2.93 (1H, m), 2.49 (2H, m), 2.40 (3H, s) 397 [336]

method: 3, RT: 2.53 min, MI: 427 [M + 1] 398 [336]

method: 3, RT: 2.47 min, MI: 427[M + 1] 399 [336]

method: 5, RT: 4.82 min, MI: 500 [M + 1] 400 [336]

method: 5, RT: 2.95 min, MI: 430 [M + 1] 401 [336]

method: 5, RT: 3.68 min, MI: 428 [M + 1] 402 [336]

method: 5, RT: 3.98 min, MI: 462 [M + 1] 1H NMR (DMSO, 300 MHz): 8.80(1H, s, br), 8.68 (2H, d), 8.48 (1H, s), 8.38 (1H, s), 8.05 (2H, d),7.63 (2H, d), 7.47 (2H, m), 7.35 (4H, m), 3.94 (1H, d), 3.50 (2H, m),2.94 (1H, dd), 2.82 (1H, dd) 403 [351]

method: 5, RT: 1.97 min, MI: 364 [M + 1] 1H NMR (DMSO, 300 MHz): 8.76(2H, dd), 8.68 (1H, d), 8.44 (1H, s), 8.38 (2H, dd), 8.31 (1H, s), 7.79(1H, d), 7.37 (1H, d), 5.01 (1H, m), 3.60 (1H, dd), 3.29 (2H, m), 2.49(2H, m), 2.32 (1H, m), 2.15 (1H, m) 404 [336]

method: 5, RT: 3.13 min, MI: 432 [M + 1] 405 [336]

method: 6, RT: 5.99 min, MI: 428 [M + 1] 1H NMR (DMSO, 300 MHz): 8.66(2H, dd), 8.46 (1H, s, br), 8.34 (1H, s), 8.01 (2H, dd), 7.95 (1H, s),7.35 (5H, m), 6.81 (1H, d), 6.47 (1H, dd), 3.91 (2H, d, br), 3.51 (2H,m), 2.91 (1H, dd), 2.81 (1H, dd), 1.64 (1H, m), 0.85 (2H, m), 0.56 (2H,m). 406 [336]

method: 5, RT: 4.28 min, MI: 444 [M + 1] 407 [336]

method: 6, RT: 5.95 min, MI: 402 [M + 1] 1H NMR (DMSO, 300 MHz): 8.66(2H, dd), 8.32 (1H, s), 8.10 (1H, s), 8.04 (2H, dd), 7.36 (5H, m), 6.88(1H, dd), 6.00 (1H, m), 3.91 (2H, d, br), 3.49 (3H, m), 2.88 (1H, dd),2.81 (1H, dd), 1.97 (2H, dd), 1.92 (1H, dd). 408 [336]

method: 5, RT: 3.26 min, MI: 388 [M + 1] 409 [336]

method: 5, RT: 4.01 min, MI: 456 [M + 1] 1H NMR (DMSO, 300 MHz): 8.83(1H, s), 8.67 (2H, d), 8.41 (1H, s), 8.36 (1H, s), 8.17 (2H, t), 7.97(2H, d), 7.38 (5H, m), 4.00 (1H, m), 3.64 (2H, m), 3.08 (1H, dd), 2.89(1H, dd). 410 [336]

method: 5, RT: 2.24 min, MI: 439 [M + 1] 411 [336]

method: 5, RT: 3.02 min, MI: 442 [M + 1] 412 [336]

method: 5, RT: 4.01 min, MI: 442 [M + 1] 413 [336]

method: 5, RT: 3.36 min, MI: 402 [M + 1] 1H NMR (DMSO, 300 MHz): 8.66(2H, d), 8.37 (1H, s), 8.02 (2H, d), 7.59 (1H, s), 7.35 (5H, m), 3.93(1H, m), 3.52 (2H, m), 2.93 (1H, dd), 2.82 (1H, dd), 2.38 (2H, m), 1.00(3H, m) 414 [BB-   39a]

method: 5, RT: 2.96 min, MI: 428 [M + 1] 415 [336]

method: 5, RT: 3.07 min, MI: 442 [M + 1] 1H NMR (DMSO, 300 MHz): 8.72(1H, s), 8.70 (2H, d), 8.39 (1H, s), 8.34 (1H, s), 8.03 (2H, d), 7.81(1H, d), 7.37 (5H, m), 3.92 (3H, s), 3.56 (3H, m), 2.93 (1H, dd), 2.77(1H, m) 416 [BB-    33]

method: 5, RT: 3.42 min, MI: 446 [M + 1] 1H NMR (DMSO, 300 MHz): 8.73(d, 1H), 8.57 (d, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.03 (m, 1H), 7.74(s, 1H), 7.27 (m, 5H), 3.70 (m, 1H), 2.75 (m, 1H), 2.64 (m, 1H). 417[336]

method: 6, RT: 6.53 min, MI: 438 [M + 1] 1H NMR (DMSO, 300 MHz): 8.67(3H, d, br), 8.42 (1H, s), 8.30 (2H, s), 8.12 (2H, d), 8.00 (2H, d),7.53 (2H, t), 7.40-7.37 (5H, m), 4.00 (1H, m), 3.58 (2H, m), 3.00 (1H,dd), 2.86-2.81 (1H, m). 418 [336]

method: 5, RT: 3.48 min, MI: 468 [M + 1] 1H NMR (DMSO, 300 MHz): 8.69(2H, d), 8.64 (1H, s, br), 8.35 (1H, s), 8.27 (2H, s, br), 8.03 (2H, d),7.42- 7.36 (5H, m), 6.95 (1H, s), 4.00 (1H, d, br), 3.71-3.58 (2H, m),3.13 (1H, dd), 2.84 (1H, dd), 2.03- 1.98 (1H, m), 0.98-0.92 (2H, m),0.78-0.73 (2H, m) 419 [BB-    33]

method: 6, RT: 5.23 min, MI: 445 [M + 1] 420 [BB-    33]

method: 5, RT: 5.61 min, MI: 445 [M + 1] 1H NMR (DMSO, 300 MHz): 8.26(s, 1H), 8.70 (d, 1H), 8.53 (d, 1H), 7.96 (s, 1H), 7.91 (m, 1H), 7.30(m, 5H), 6.83 (d, 1H), 6.68 (d, 1H), 3.66 (m, 1H), 2.74 (m, 2H), 2.62(m, 2H) 421 [BB-    33]

method: 5, RT: 4.32 min, MI: 514 [M + 1] 422 [BB-    33]

method: 5, RT: 3.4 min, MI: 458 [M + 1] 423 [BB-    33] 0r [304]

method: 5, RT: 3.03 min, MI: 457 [M + 1] 424 [BB-    33]

method: 5, RT: 3.61 min, MI: 486 [M + 1] 425 [BB-    33]

method: 5, RT: 3.7 min, MI: 486 [M + 1] 426 [BB-    33]

method: 5, RT: 4.02 min, MI: 446 [M + 1] 427 [BB-    33]

method: 5, RT: 2.51 min, MI: 485 [M + 1] 428 [BB-    33]

method: 5, RT: 3.44 min, MI: 475 [M + 1] 1H NMR (MeOD, 300 MHz): 8.58(d, 1H), 8.52 (s, 1H), 8.49 (d, 1H), 7.93 (m, 1H), 7.32 (m, 5H), 3.95(m, 2H), 3.77 (m, 1H), 3.03 (m, 2H), 2.43 (s, 3H), 2.27 (s, 3H). 429[BB-    33]

method: 5, RT: 2.64 min, MI: 457 [M + 1] 430 [BB-    33]

method: 5, RT: 4.21 min, MI: 474 [M + 1] 431 [BB-    33]

method: 5, RT: 4.12 min, MI: 462 [M + 1] 1H NMR (DMSO, 300 MHz): 8.62(m,2H), 8.52 (m, 2H), 8.08(dd, 1H), 7.8 (dd, 1H), 7.48(dd, 1H), 7.35 (m,5H), 4.03 (m, 2H), 3.93 (m, 2H), 3.76 (m, 1H) 432 [BB-    33]

method: 5, RT: 4.07 min, MI: 446 [M + 1] 433 [BB-    33]

method: 5, RT: 4.02 min, MI: 470 [M + 1] 434 [BB-    33]

method: 5, RT: 4.11 min, MI: 456 [M + 1] 435 [BB-    33]

method: 5, RT: 2.51 min, MI: 475 [M + 1] 436 [334]

method: 4, RT: 5.49 min, MI: 512 [M + 1] 437 [334]

method: 4, RT: 3.82 min, MI: 484 [M + 1] 438 [300]

method: 4, RT: 4.24 min, MI: 471 [M + 1] 439 [300]

method: 4, RT: 3.37 min, MI: 483 [M + 1] 1H NMR (DMSO, 300 MHz):8.59(dd, 2H), 8.53 (d, 1H), 8.36(d, 2H), 7.86(d, 2H), 7.33(m, 5H), 7.25(d, 1H), 3.81 (s, 3H), 3.45 (m, 2H), 2.81 (m, 3H), 2.44 (s, 3H) 440[300]

method: 4, RT: 4.49 min, MI: 540 [M + 1] 441 [334]

method: 4, RT: 5.35 min, MI: 524 [M + 1] 442 [334]

method: 4, RT: 5.51 min, MI: 512 [M + 1] 443 [334]

method: 4, RT: 4.79 min, MI: 513 [M + 1] 444 [334]

method: 4, RT: 4.57 min, MI: 509 [M + 1] 445 [334]

method: 4, RT: 5.07 min, MI: 484 [M + 1] 446 [300]

method: 4, RT: 4.80 min, MI: 528 [M + 1] 1H NMR (DMSO, 300 MHz): 8.62(dd, 2H), 7.90 (dd, 2H), 7.46 (m, 1H), 7.29 (m, 5H), 7.27 (m, 1H), 7.16(m, 1H), 3.84 (m, 2H), 3.16 (d, 6H), 2.92 (m, 2H), 2.81 (m, 1H), 2.65(m, 1H), 2.53 (s, 3H) 447 [334]

method: 4, RT: 5.72 min, MI: 514 [M + 1] 448 [334]

method: 4, RT: 4.45 min, MI: 523 [M + 1] 449 [300]

method: 4, RT: 4.51 min, MI: 452 [M + 1] 1H NMR (DMSO, 300 MHz): 8.62(dd, 2H), 7.90 (dd, 2H), 7.57 (m, 5H), 7.34 (m, 5H), 3.5 (m, 1H), 2.92(m, 2H), 2.81 (m, 1H), 2.65 (m, 1H), 2.6 (s, 3H) 450 [300]

method: 4, RT: 4.59 min, MI: 496 [M + 1] 451 [334]

method: 4, RT: 5.51 min, MI: 494 [M + 1] 452 [300]

method: 4, RT: 5.02 min, MI: 554 [M + 1] 453 [300]

method: 4, RT: 4.41 min, MI: 516 [M + 1] 454 [300]

method: 4, RT: 4.12 min, MI: 512 [M + 1] 455 [330]

method: 4, RT: 4.74 min, MI: 554 [M + 1] 456 [300]

method: 4, RT: 3.45 min, MI: 483 [M + 1] 457 [300]

method: 4, RT: 3.73 min, MI: 487 [M + 1] 458 [300]

method: 4, RT: 5.03 min, MI: 524 [M + 1] 1H NMR (DMSO, 300 MHz): 8.6(dd, 2H), 7.85 (dd, 2H), 7.34 (m, 5H), 7.17 (m, 1H), 7.03 (m, 2H), 3.5(m, 1H), 2.92 (m, 2H), 2.81 (m, 2H), 2.53 (d, 6H), 2.65 (m, 1H), 2.41(s, 3H), 2.3 (s, 3H) 459 [300]

method: 4, RT: 3.49 min, MI: 467 [M + 1] 460 [300]

method: 4, RT: 5.13 min, MI: 544 [M + 1] 1H NMR (DMSO, 300 MHz): 8.62(dd, 2H), 7.92 (dd, 2H), 7.44 (m, 5H), 7.32 (m, 1H), 7.28 (m, 2H), 7.19(m, 2H), 3.5 (m, 1H), 2.92 (m, 2H), 2.81 (m, 2H), 2.65 (m, 1H), 2.53 (d,6H), 2.42 (s, 3H) 461 [300]

462 [300]

method: 4, RT: 5.14 min, MI: 524 [M + 1] 463 [300]

method: 4, RT: 4.91 min, MI: 530 [M + 1] 464 [300]

method: 4, RT: 4.73 min, MI: 550 [M + 1] 465 [300]

method: 4, RT: 3.96 min, MI: 483 [M + 1] 1H NMR (DMSO, 300 MHz): 8.6(dd, 2H), 8.28 (dd, 1H), 7.82 (dd, 2H), 7.72 (m, 1H), 7.34 (m, 5H), 7.15(m, 1H), 3.82 (s, 3H), 3.5 (m, 3H), 2.93 (m, 1H), 2.82 (m, 1H), 2.43 (s,3H) 466 [300]

method: 4, RT: 4.24 min, MI: 512 [M + 1] 467 [300]

method: 4, RT: 4.35 min, MI: 500 [M + 1] 468 [334]

method: 4, RT: 3.83 min, MI: 484 [M + 1] 469 [BB-    41]

method: 3, RT: 2.26 min, MI: 392 [M + 1] ^(a)site of attachment tothieno pyrimidine core. b Clapham, Kate M.; Batsanov, Andrei S.; Bryce,Martin R.; Tarbit, Brian, Organic and Biomolecular Chemistry, 2009, vol.7, p. 2155-216

General Synthesis of 7-amido-4PT32P Derivatives of General Formula[G-128](Scheme B6)

A 7-unsubstituted 2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol of generalformula [G-124] was nitrated at the C-7 position by reaction with anitrating agent such as fuming nitric acid in concentrated sulphuricacid to yield the corresponding 7-nitro-substituted 4PT32P derivative ofgeneral formula [G-125]. The 7-nitro-4PT32P derivative was then reducedto the corresponding 7-amino PT32P derivative of general formula [G-126]by hydrogenation reaction under an atmosphere of hydrogen in thepresence of a catalyst such as palladium on activated charcoal. Amideformation was performed by reaction with an acyl chloride, of generalformula [G-129] with the 7-amino-4PT32P derivative [G-126] to yield thecorresponding 7-amidosubstituted 4PT32P derivative of general formula[G-127]. The intermediate 7-amidosubstituted 4PT32P derivative ofgeneral formula [G-127] was then reacted with2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solventsuch as DMA, DMF, NMP with a tertiary alkylamine base such as Et₃N,DIPEA or NMM and a catalytic amount of DMAP, and the intermediate7-amidosubstituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester was used crudeand reacted further with a primary or secondary amino derivative, ofgeneral formula [G-117], in a polar aprotic solvent such as DMA, DMF,NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMMat ambient temperature. After reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release, the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, TCA, methanesulfonic acid,HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH and thecrude reaction product was purified by reverse phase preparative HPLC.

Synthesis of 7-nitro-2-Pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-40]

To a stirred solution of 2-Pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol[BB-13](5 g, 21.8 mmol) in concentrated sulfuric acid (50 ml) at 0° C.was added fuming nitric acid (5 ml) dropwise. The reaction mixture wasleft to stir at 0° C. for 1 hr then the mixture was poured onto ice andleft to stir at room temperature overnight. The pale yellow precipitatewas collected by filtration, and washed with H₂O followed by THF, toyield the title compound as a pale yellow solid (1.84 g, 31% yield)which was used in the next step without further purification: LCMSmethod 3, 2.94 min, 100%, 274.97 [M+H]

Synthesis of 7-Amino-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-41]

7-Nitro-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-40] (4.25 g, 15.5mmol) was dissolved in 2:3 mixture of MeOH-DMF (500 ml) and filteredthrough a PTFE phase separation frit to remove any undissolved solids.The filtrate was then loaded onto an H-cube with a flow rate of 1 ml/min[using a paladium on activated charcoal cartridge at room temperatureand an atmospheric pressure of H₂]. The crude reaction mixture wasevaporated under reduced pressure to remove the MeOH and the resultingDMF solution was poured onto an SCX cartridge, which was washed withMeOH followed by NH₃:MeOH. The methanolic ammonia flush was concentratedin vacuo to provide the title compound as a brown solid (1.5 g, 40%yield) which was used in the next step without further purification:LCMS method 3, 2.35 min, 100%, 244.99 [M+H]

Synthesis of Cyclopentanecarboxylic acid[2-pyridin-4-yl-4-((R)-pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-7-yl]-amide[470]

7-Amino-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-41] (100 mg, 0.42mmol) was dissolved in DMA (2 ml) and DIPEA (150 μL). The reactionmixture was cooled to 0° C. and a mixture of cyclopentane carbonylchloride (100 μL, 0.84 mmol) in DMA (1 ml) was added and the reactionwas left to stir at 0° C. for 2 hours. The mixture was treated withwater (1 ml) and left to stir for 2 hours at room temperature. The crudereaction mixture was extracted with DCM (2 ml) and washed with brine (3ml) and the organic extract was then loaded on a SCX-2 cartridge, whichwas washed with MeOH followed by NH₃:MeOH. The methanolic ammonia flushwas concentrated under reduced pressure to providecyclopentanecarboxylic acid(4-hydroxy-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl)-amide [BB-42],which was used crude in the next step. To a solution of crudecyclopentanecarboxylic acid(4-hydroxy-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl)-amide [BB-42] (70mg, 0.21 mmol), DMAP (3 mg), TEA (60 ml, 0.42 mmol) in DMA (5 ml) wasadded 2,4,6-triisopropylbenzenesulfonyl chloride (77 mg, 0.25 mmol). Themixture was left to stir at room temperature overnight. A mixture of(R)-(+)-1-Boc-3-aminopyrrolidine (40 ml, 0.21 mmol) in DMA (1 ml) wasadded and the mixture was left to stir at room temperature for 24 hours.Water was added and the reaction mixture was extracted with DCM and theextract was dried (MgSO₄), filtered and evaporated under reducedpressure. The crude product was dissolved in DCM (2 ml) and TFA (1 ml)was added, the mixture was left to stir at room temperature for 1 hourthen the crude reaction mixture was loaded on to a SCX-2 cartridge,which was washed with MeOH followed by NH₃:MeOH. The methanolic ammoniaflush was concentrated in vacuo and the residue was purified bypreparative LC-MS to provide the title compound. LCMS method 5, 2.71min, 409 [M+H].

The following compounds were prepared according to the general synthesisshown in Scheme B6:

      Ex- am- ple           SM         Amine [F117]

  [F-129]         Character- isation 471 [BB- 41]

LCMS method 5, 3.00 min, 411 [M + H] 472 [BB- 41]

LCMS method 5, 4.01 min, 475 [M + H] 473 [BB- 41]

LCMS method 5, 3.09 min, 423 [M + H] 474 [BB- 41]

LCMS method 5, 4.39 min, 487 [M + H] 475 [BB- 41]

LCMS method 5, 3.91 min, 473 [M + H]

General Synthesis of 4-alkoxy-substituted 4PT32P Derivative of GeneralFormula [G-130] (Scheme B7)

The Polystyrene supported benzenesulfonic acid 6,7substituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester of generalformula [G-118] [prepared in scheme B5] was subjected to a nucleophilicsubstitution reaction with an amino alcohol, of general formula [G-131],in the presence of a strong base such as NaH, KH or LDA in an anhydrouspolar aprotic solvent such as DMA, DMF or NMP. After reaction work up,typically filtration of the resin through a PTFE frit followed by aliquid-liquid extraction or purification by acidic ion exchangecatch-release, the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, TCA, methanesulfonic acid,HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH and thecrude reaction product was purified by reverse phase preparative HPLC.

Synthesis of7-methyl-2-pyridin-4-yl-4-((R)-1-pyrrolidin-2-ylmethoxy)-thieno[3,2-d]pyrimidine[476]

7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-05] (70 mg, 0.28mmol) and PS-TSCl (210 mg, 0.45 mmol) were placed into filter cartridgeclosed with a stopper. DMA (2 ml) was added followed by Et₃N (70 μl, 0.5mmol) and DMAP (1.1 mg, 0.009 mmol). The reaction was shaken for 3 hoursat room temperature and then the polymer was filtered through a PTFEfrit. The resin was washed with DCM, DMA, DCM to yield to theintermediate polystyrene supported benzenesulfonic acid7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-43], whichwas used in the next step without further purification.

Polymer supported benzenesulfonic acid7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester [BB-43] (0.280mmol) was placed in a filter cartridge and DMA (2 ml) was added,followed by (R)-(+)-1-boc-2-pyrrolidinemethanol (68 μl, 0.340 mmol) andNaH (14 mg, 0.340 mmol). The reaction was shaken overnight at roomtemperature. The resin was filtered through a PTFE frit and washed withethylacetate. The filtrates were combined and concentrated under reducedpressure. The crude product was dissolved in DCM (2 ml) and TFA (2 ml)was added and the mixture was stirred at room temperature for 1 hour.After completion the mixture was loaded onto a SCX-2 cartridge andwashed with methanol. The product was released from the cartridge usinga solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product was purifiedby preparative HPLC (method A) to yield to the title compound. LCMSmethod: 2, RT: 1.91 min, MI: 313 [M+1].

The following compounds were prepared according to the general synthesisshown in scheme B7:

ROH Example SM [G-131] Characterisation 477 [BB- 09]

method: 2, RT: 3.47 min, MI: 447 [M + 1] 478 [BB- 09]

method: 2, RT: 3.29 min, MI: 397 [M + 1] 479 [BB- 09]

method: 2, RT: 2.28 min, MI: 397 [M + 1] 480 [BB- 05]

method: 2, RT: 1.95 min, MI: 327 [M + 1] 481 [BB- 05]

method: 2, RT: 2.80 min, MI: 377 [M + 1] 482 [BB- 05]

method: 2, RT: 2.80 min, MI: 377 [M + 1] 483 [BB- 05]

method: 2, RT: 1.92 min, MI: 313 [M + 1] 484 [BB- 05]

method: 2, RT: 1.91 min, MI: 313 [M + 1]

General Synthesis of 7-arylaminosubstituted-4PT32P Derivatives ofGeneral Formula [F-132] (Scheme B8)

The 7-bromo-6-substituted-2-pyridin-4-yl-thieno[3,2-d]pyrimidinederivative of general formula [G-119] was involved in a Buchwald typereaction utilising a suitable amine, of general formula [G-133], apalladium catalyst such as Pd(dba)₂ or Pd(OAc)₂, a ligand such asXantphos and a base such as NaOtBu or Cs₂CO₃ in a polar solvent such asdioxane or a combination of dioxane and DMA at high temperature eitherby heating thermally or using a microwave reactor. After reaction workup, typically by a liquid-liquid extraction or purification by acidicion exchange catch-release, the N-Boc derivatives were deprotected underacidic conditions with a strong acid such as TFA, TCA, methanesulfonicacid, HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH andthe crude reaction product was purified by preparative reverse phaseHPLC.

Synthesis ofN*4*-((S)-2-Amino-3-phenyl-propyl)-N*7*-phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidine-4,7-diamine[485]

A microwave vial was charged with(S)—N*1*-(7-bromo-6-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[336](100 mg, 0.227 mmol), aniline (27 μl, 0.295 mmol), Pd(dba)₂ (7 mg,0.011 mmol), Xantphos (13 mg, 0.023 mmol), NaOtBu (45 mg, 0.454 mmol),DMA (few drops) and dioxane (1 ml). The reaction was heated to 150° C.for 15 minutes under microwave irradiation. The mixture was then loadedonto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method B) to yield thetitle compound. LCMS method: 4, RT: 4.38 min, MI: 453 [M+1]. ¹H NMR (300MHz, DMSO): 8.68 (2H, d), 8.41 (1H, s, br), 8.24 (2H, d), 8.17 (1H, s),7.34 (9H, m), 6.87 (1H, t), 3.89 (1H, m, br), 3.40 (2H, t), 2.78 (2H,d).

The following compounds were prepared according to the general synthesisshown in Scheme B8:

RxRyNH Example SM [G-133] Characterisation 486 [336]

method: 5, RT: 3.06 min, MI: 454 [M + 1] 487 [351]

method: 5, RT: 1.60 min, MI: 390 [M + 1] 1H NMR (300, MHz, DMSO): 9.07(1H, s), 8.76 (2H, d), 8.54 (2H, d), 8.39 (2H, t), 8.26 (1H, d), 7.66(1H, t), 7.35 (1H, d), 6.84 (1H, t), 4.90 (1H, m), 3.44 (2H, m), 3.09(2H, m) 2.25 (1H, m), 1.88 (1H, m) 488 [336]

method: 5, RT: 3.33 min, MI: 455 [M + 1] 1H NMR (300, MHz, DMSO): 9.02(1H, s), 8.67 (2H, s, br), 8.61 (2H, d), 8.25 (1H, s), 8.18 (2H, d),7.35 (5H, m), 6.98 (2H, t), 3.95 (1H, m), 3.49 (2H, m), 2.93 (1H, m),2.81 (1H, m) 489 [336]

method: 5, RT: 3.22 min, MI: 455 [M + 1] 490 [336]

method: 5, RT: 3.29 min, MI: 458 [M + 1] 491 [BB-33]

method: 5, RT: 4.15 min, MI: 471 [M + 1] 1H NMR (300, MHz, MeOD): 8.62(d, 1H), 8.53 (s, 1H), 8.51 (d, 1H), 8.12 (m, 10H), 3.95 (m, 2H), 3.76(m, 1H), 3.04 (m, 2H). 492 [352]

method: 5, RT: 3.89 min, MI: 421 [M + 1] 493 [352]

method: 5, RT: 3.64 min, MI: 425 [M + 1] 494 [352]

method: 5, RT: 1.19 min, MI: 408 [M + 1] 495 [352]

method: 5, RT: 2.08 min, MI: 408 [M + 1] 496 [352]

method: 5, RT: 3.07 min, MI: 412 [M + 1] 497 [352]

method: 5, RT: 2.82 min, MI: 398 [M + 1] 498 [352]

method: 5, RT: 3.95 min, MI: 421 [M + 1] 1H NMR (300, MHz, MeOD): 8.6(1H, d), 8.52 (1H, d), 8.48 (1H, s), 8.27 (1H, m), 7.23 (2H, d), 7.35(1H, d), 6.92 (1H, m), 4.9 (1H, m), 3.44 (2H, m), 3.09 (2H, m), 2.25(1H, m), 1.88 (1H, m) 499 [352]

method: 5, RT: 3.69 min, MI: 425 [M + 1] 500 [352]

method: 5, RT: 3.8 min, MI: 425 [M + 1] 1H NMR (300, MHz, MeOD): 8.61(1H, d), 8.53 (1H, d), 8.49 (1H, s), 8.28 (1H, m), 7.24 (2H, d), 7.34(1H, d), 6.91 (1H, m), 4.91 (1H, m), 3.44 (2H, m), 3.08 (2H, m), 2.27(1H, m), 1.88 (1H, m)

General Synthesis of 7-alkynyl-substituted-4PT32P and 6-alkynylsubstituted-4PT32P Derivatives of General Formula [F134] & [G-135](Scheme B9)

The7-Bromo-6-substituted-4-amino-2-(3-substituted-pyridin-4-yl)-thieno[3,2-d]pyrimidinederivative of general formula [G-119] or6-Bromo-6-substituted-4-amino-2-(3-substituted-pyridin-4-yl)-thieno[3,2-d]pyrimidinederivative of general formula [G-121] was involved in a Sonogashiracoupling reaction utilising a suitable terminal alkyne, of generalformula [G-136], in the presence of copper(I)iodide with Pd(PPh₃)₂Cl₂ ascatalyst, triphenylphosphine as ligand, and a base such as Et₃N, or DEAin a polar solvent such as DMA or DMF at a high temperature either byheating thermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the N-Boc derivatives were deprotected underacidic conditions with a strong acid such as TFA, HCl in a solvent suchas DCM, DCE or 1,4-dioxane or by catch and release sulfonic acidicresins such as polymer supported toluene sulfonic acid. In the case ofsilyl protected acetylenes, a further deprotection using 1M TBAF in THFwas used prior to the acid mediated cleavage of the Boc group and thecrude reaction mixtures were purified by preparative reverse phase HPLC.

Synthesis of4-[4-((S)-2-Amino-3-phenyl-propylamino)-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7-yl]-but-3-yn-1-ol[501]

A microwave vial was charged with{(S)-1-Benzyl-2-[7-bromo-2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-carbamicacid tert-butyl ester [BB-33] (100 mg, 0.179 mmol), 3-butyn-1-ol (15 μL,0.197 mmol), bis(triphenylphosphine)palladiumchloride (13 mg, 0.018mmol), copper(I)Iodide (3.4 mg, 0.018 mmol), triphenylphosphine (9.4 mg,0.036 mmol), diethylamine (0.28 ml, 2.686 mmol) and DMF (1 ml). Thereaction mixture was heated to 150° C. for 15 minutes under microwaveirradiation. After completion, the product was extracted with ethylacetate (2×2 ml), washed with brine (2 ml) and the combined organicphases were dried (MgSO₄), filtered and evaporated under reducedpressure. The crude product was dissolved in DCM (2 ml) and TFA (1 ml)was added, the mixture was stirred at room temperature for 1 hour thenthe crude product was loaded onto an SCX cartridge and the cartridge waswashed with methanol then the product was eluted with 2Mammonia/methanol. The eluent was concentrated under reduced pressure andthe crude mixture purified by preparative HPLC (method A) to yield thetitle compound: LCMS method: 7, RT: 3.15 min, MI: 448 [M+1]. ¹H NMR(300, MHz, DMSO): 8.69 (d, 1H), 8.55 (d, 1H), 8.28 (s, 1H), 7.90 (m,1H), 7.24 (m, 5H), 4.92 (bs, 1H), 3.62 (m, 2H), 2.78 (m, 1H), 2.62 (m,2H).

Synthesis of2-Methyl-4-[7-methyl-2-pyridin-4-yl-4-((R)-pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-but-3-yn-2-ol[502]

A microwave vial was charged with(R)-3-(6-Bromo-7-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-35] (60 mg, 0.13 mmol), 2-methyl-3-butyn-1-ol(51 μL, 0.53 mmol), bis(triphenylphosphine)palladiumchloride (93 mg,0.13 mmol), copper(I)Iodide (25 mg, 0.13 mmol), triphenylphosphine (70mg, 0.26 mmol), diethylamine (0.2 ml, 1.9 mmol) and DMF (1 ml). Thereaction mixture was heated to 150° C. for 10 minutes under microwaveirradiation. After completion, the product was extracted with ethylacetate (2×2 ml), washed with brine (2 ml) and the combined organicphases were dried (MgSO₄), filtered and evaporated under reducedpressure. The crude product was dissolved in DCM (2 ml) and TFA (1 ml)was added, the mixture was stirred at room temperature for 1 hour thenthe crude product was loaded onto an SCX cartridge and the cartridge waswashed with methanol then the product was eluted with 2Mammonia/methanol. The eluent was concentrated under reduced pressure andthe crude mixture purified by preparative HPLC (method A) to yield thetitle compound. LCMS method 5, 2.83 min, 394 [M+H].

The following compounds were prepared according to the general synthesisshown in Scheme B9:

Terminal alkyne Ex SM [G-136] Characterisation 503 [328]

method: 5, RT: 2.41 min, MI: 394 [M + 1] 504 [300]

method: 5, RT: 3.28 min, MI: 458 [M + 1] 505 [334]

method: LC-MS15QC, RT: 5.93 min, MI: 500 [M + 1] 506 [BB-33]

method: 5, RT: 3.02 min, MI: 434 [M + 1] 1H NMR (300 MHz, DMSO): 8.68(1H, d), 8.56 (1H, dd), 8.38 (1H, s), 7.89 (1H, m), 7.24 (5H, m), 4.35(2H, s), 3.67 (2H, m), 3.25 (2H, m), 2.77 (1H, m), 2.58 (1H, m) 507[BB-33]

method: 5, RT: 3.55 min, MI: 474 [M + 1] 1H NMR (300 MHz, MeOD): 8.62(d, 1H), 8.53 (d, 1H), 8.47 (s, 1H), 8.20 (s, 1H), 7.98 (m, 1H), 7.31(m, 5H), 4.62 (s, 2H), 3.95 (m, 2H), 3.74 (m, 1H), 3.02 (d, 2H), 2.55(m, 2H), 2.35 (m, 2H), 1.89 (m, 2H) 508 [BB-33]

method: 5, RT: 3.32 min, MI: 448 [M + 1] 1H NMR (300 MHz, DMSO): 8.68(d, 1H), 8.53 (d, 1H), 8.35 (s, 1H), 7.84 (dd, 1H), 7.25 (m, 5H), 4.62(q, 1H), 3.71 (m, 1H), 3.45 (m, 2H), 2.80 (m, 2H), 1.39 (d, 3H) 509[BB-33]

method: LC-MS15QC, RT: 5.58 min, MI: 462 [M + 1] 1H NMR (300 MHz, DMSO):8.68 (d, 1H), 8.53 (d, 1H), 8.31 (s, 1H), 7.91 (t, 1H), 7.25 (m, 5H),3.68 (m, 1H), 2.75 (m, 2H), 2.60 (m, 2H), 1.49 (s, 6H) 510 [BB-34]

method: 6, RT: 4.87 min, MI: 444 [M + 1] 1H NMR (DMSO, 300 MHz): 8.77(1H, s, br), 8.68 (2H, d), 8.37 (1H, s, br), 8.29 (1H, s), 8.00 (2H, d),7.36 (5H, m), 3.93 (1H, d, br), 3.50 (2H, m), 2.93 (1H, dd), 2.82 (1H,m), 1.53 (6H, s) 511 [BB-34]

method: 5, RT: 4.01 min, MI: 442 [M + 1] 512 [336]

method: 5, RT: 3.41 min, MI: 426 [M + 1] 513 [336]

method: 5, RT: 2.84 min, MI: 430 [M + 1] 1H NMR (DMSO, 300 MHz) 8.75(2H, s, br), 8.37 (1H, t), 8.30 (1H, s), 8.13 (2H, s, br), 7.39 (5H, m),4.70 (1H, q), 3.93 (1H, dd), 3.65 (2H, m), 3.13 (1H, dd), 1.45 (3H, d)514 [351]

method: 5, RT: 2.10 min, MI: 380 [M + 1] 1H NMR (DMSO, 300 MHz) 8.75(2H, d), 8.66 (1H, d), 8.35 (2H, d), 4.98 (1H, m), 3.60 (1H, m), 3.31(2H, m), 2.35 (2H, m), 2.12 (2H, m), 1.56 (6H, s) 515 [BB-34]

method: 5, RT: 2.59 min, MI: 416 [M + 1] 1H NMR (DMSO, 300 MHz) 8.68(2H, d), 8.37 (1H, s), 8.01 (2H, d), 7.36 (5H, m), 4.40 (2H, s), 3.95(2H, m), 3.49 (2H, m), 2.95 (1H, m), 2.77 (1H, m) 516 [336]

method: 5, RT: 2.16 min, MI: 443 [M + 1] 1H NMR (DMSO, 300 MHz) 8.69(2H, d), 8.27 (1H, s, br), 8.21 (1H, s), 8.11 (2H, d), 7.33-7.26 (5H,m), 3.82 (1H, m), 3.30 (2H, m), 2.71 (2H, m), 1.44 (6H, s) 517 [351]

method: 5, RT: 1.83 min, MI: 366 [M + 1] 1H NMR (DMSO, 300 MHz): 8.75(2H, d), 8.59 (1H, s), 8.34 (2H, d), 4.91 (1H, m), 4.70 (1H, m), 3.46(1H, m), 3.23 (1H, m), 3.16 (1H, m), 2.27 (1H, m), 2.07 (2H, m), 1.46(3H, d) 518 [336]

method: 5, RT: 3.73 min, MI: 428 [M + 1] 1H NMR (DMSO, 300 MHz): 8.68(2H, d), 8.46 (1H, s), 8.24 (1H, s), 8.05 (2H, d), 7.33 (5H, m), 3.89(1H, m), 2.91 (1H, m), 2.81 (1H, m), 1.29 (3H, s), 1.27 (3H, s) 519[352]

method 6, 4.79 min, 398 [M + H] 520 [336]

method: 5, RT: 3.48 min, MI: 458 [M + 1] 1H NMR (DMSO, 300 MHz): 8.69(2H, d), 8.36 (1H, s), 8.05 (2H, d), 7.35-7.29 (5H, m), 3.87 (1H, m),3.45 (3H, s), 2.79-2.71 (2H, m), 1.53 (6H, s) 521 [336]

method: 5, RT: 3.17 min, MI: 444 [M + 1] 1H NMR (DMSO, 300 MHz): 8.68(2H, d), 8.47 (1H, s), 8.32 (1H, s), 8.27 (1H, s), 8.05 (2H, d),7.35-7.29 (5H, m), 4.48 (1H, t), 3.88 (1H, d, br), 3.41 (2H, m),2.89-2.77 (2H, m), 1.77-1.67 (2H, m), 1.08 (3H, t) 522 [336]

method: 6, RT: 6.22 min, MI: 486 [M + 1] 1H NMR (DMSO, 300 MHz): 8.67(2H, d), 8.51 (1H, s, br), 8.31 (1H, s), 8.05 (2H, d), 7.36-7.28 (5H,m), 4.40 (1H, dd), 3.89 (1H, m), 3.42 (2H, m), 2.81 (2H, m), 1.72 (2H,m), 1.43 (1H, m), 1.31 (2H, m), 1.04 (3H, m), 0.89 (3H, t) 523 [336]

method: LC-MS15QC, RT: 5.80 min, MI: 458 [M + 1] 524 [336]

method: 5, RT: 3.60 min, MI: 472 [M + 1] 525 [336]

method: 5, RT: 3.70 min, MI: 472 [M + 1] 526 [336]

method: 5, RT: 3.46 min, MI: 458 [M + 1] 1H NMR (DMSO, 300 MHz): 8.67(2H, d), 8.52 (1H, s, br), 8.30 (1H, s), 8.26 (1H, s), 8.03 (2H, d),7.38-7.31 (5H, m), 4.54 (1H, t), 3.90 (1H, m), 3.49 (2H, m), 2.90-2.81(2H, m), 1.71-1.56 (4H, m), 0.97 (3H, s) 527 [352]

method: 5, RT: 2.44 min, MI: 384 [M + 1] 1H NMR (DMSO, 300 MHz): 8.02(dd, 1H), 8.21 (bs, 1H), 8.70 (d, 1H), 8.55 (d, 1H), 8.47 (s, 1H), 4.64(q, 1H), 3.88 (m, 1H), 3.66 (m, 2H), 3.12 (m, 2H), 2.24 (m, 1H), 2.19(m, 1H), 1.43 (d, 3H) 528 [BB-34]

method: 5, RT: 3.48 min, MI: 470 [M + 1] 1H NMR (DMSO, 300 MHz): 8.70(1H, s, br), 8.68 (2H, d), 8.35 (1H, s), 8.29 (1H, s), 8.00 (2H, d),7.36-7.33 (5H, m), 3.93 (1H, d, br), 3.46-3.41 (2H, m), 2.92 (1H, dd),2.79-2.75 (1H, m), 2.00-1.90 (4H, m), 1.75 (4H, d, br) 529 [336]

method: 5, RT: 3.27 min, MI: 463 [M + 1] 1H NMR (DMSO, 300 MHz): 9.06(1H, s, br), 8.67 (2H, d), 8.64 (1H, m), 8.60 (1H, s), 8.38 (1H, s),8.01 (2H, d), 7.89 (1H, t), 7.72 (1H, d), 7.47-7.34 (6H, m), 4.02-3.97(1H, m), 3.59-3.50 (2H, m), 3.03 (1H, dd), 2.86-2.77 (1H, m) 530 [336]

method: 5, RT: 4.00 min, MI: 480 [M + 1] 1H NMR (DMSO, 300 MHz): 8.83(1H, s, br), 8.67 (2H, d), 8.54 (1H, s), 8.37 (1H, s), 8.04 (2H, d),7.71 (1H, t), 7.53-7.48 (1H, m), 7.41-7.28 (6H, m), 3.97- 3.94 (1H, m),3.50-3.46 (2H, m), 2.95 (1H, dd), 2.84-2.77 (1H, m) 531 [336]

method: 5, RT: 2.67 min, MI: 430 [M + 1] 1H NMR (DMSO, 300 MHz): 8.79(1H, s, br), 8.67 (2H, d), 8.28 (3H, d), 7.98 (2H, d), 7.40-7.34 (5H,m), 3.97 (1H, d, br), 3.64 (2H, t), 3.54-3.48 (2H, m), 3.01 (1H, dd),2.84 (1H, m), 2.63 (2H, t) 532 [336]

method: 5, RT: 2.89 min, MI: 442 [M + 1] 1H NMR (DMSO, 300 MHz): 8.69(2H, d), 8.39 (1H, s), 8.28 (2H, d), 8.06 (2H, d), 7.35- 7.28 (5H, m),6.41 (1H, s, br), 3.86 (1H, m), 2.86 (2H, m), 2.78-2.72 (2H, m), 1.13(2H, t), 1.04 (2H, m) 533 [336]

method: 5, RT: 2.74 min, MI: 430 [M + 1] 1H NMR (DMSO, 300 MHz): 8.85(1H, s, br), 8.67 (2H, d), 8.33 (1H, s), 8.29 (2H, s, br), 7.98 (2H, d),7.41-7.36 (5H, m), 4.68 (1H, q), 3.97 (1H, d, br), 3.62- 3.51 (2H, m),2.93 (1H, dd), 2.84 (1H, dd), 1.45 (3H, s) 534 [336]

method: 5, RT: 2.76 min, MI: 430 [M + 1] 1H NMR (DMSO, 300 MHz): 8.87(1H, s, br), 8.67 (2H, d), 8.33 (1H, s), 8.29 (2H, s, br), 7.97 (2H, d),7.41-7.36 (5H, m), 4.68 (1H, q), 3.97 (1H, d, br), 3.64- 3.52 (2H, m),2.93 (1H, dd), 2.84 (1H, dd), 1.45 (3H, s) 535 [336]

method: 5, RT: 2.84 min, MI: 444 [M + 1] 1H NMR (DMSO, 300 MHz): 8.76(1H, s, br), 8.67 (2H, d), 8.35 (2H, s), 8.25 (1H, s), 7.99 (2H, d),7.39-7.32 (5H, m), 3.96 (1H, d, br), 3.61 (2H, t), 3.51-3.46 (2H, m),2.97 (1H, dd), 2.82 (1H, dd), 2.55 (2H, m), 1.74 (2H, q) 536 [336]

method: 5, RT: 2.93 min, MI: 444 [M + 1] 1H NMR (DMSO, 300 MHz): 8.77(1H, s, br), 8.66 (2H, d), 8.30 (2H, s, br), 8.26 (1H, s), 7.98 (2H, d),7.40-7.34 (5H, m), 3.96- 3.90 (2H, m), 3.60-3.49 (2H, m), 3.00 (1H, dd),2.86-2.82 (1H, m), 2.63 (1H, dd), 1.29 (3H, d) 537 [336]

method: 5, RT: 3.08 min, MI: 458 [M + 1] 1H NMR (DMSO, 300 MHz): 8.68(2H, d), 8.24 (2H, s, br), 8.09 (2H, d), 7.32-7.25 (5H, m), 4.67 (1H,s), 3.80 (1H, d, br), 3.28 (2H, m), 2.72-2.67 (2H, m), 2.58 (2H, s),1.34 (6H, s). 538 [336]

method: 5, RT: 1.44 min, MI: 429 [M + 1] 1H NMR (DMSO, 300 MHz): 8.67(2H, d), 8.31 (2H, s), 8.01 (2H, d), 7.38-7.31 (5H, m), 3.93 (1H, d,br), 3.63 (2H, s), 3.48-3.40 (2H, m), 2.93 (1H, dd), 2.80 (1H, dd), 2.45(3H, s) 539 [BB-34]

method: 5, RT: 3.18 min, MI: 456 [M + 1] 1H NMR (MeOD, 300 MHz): 8.61(2H, d), 8.25 (2H, d), 8.10 (1H, s), 7.37-7.27 (5H, m), 4.01-3.98 (1H,m), 3.58- 3.52 (2H, m), 2.86 (2H, dd), 2.65-2.55 (2H, m), 2.42-2.32 (2H,m), 1.99-1.92 (2H, m) 540 [BB-34]

method: 5, RT: 6.43 min, MI: 444 [M + 1] 1H NMR (MeOD, 300 MHz): 8.58(2H, d), 8.35 (2H, s), 8.13 (2H, d), 8.03 (1H, s), 7.41-7.35 (5H, m),4.13 (1H, dd), 4.05 (1H, q), 3.92- 3.89 (1H, m), 3.70 (1H, dd), 3.11(1H, dd), 3.00 (1H, dd), 2.66 (2H, d), 1.41 (3H, d) 541 [336]

method: 5, RT: 2.82 min, MI: 386 [M + 1] 1H NMR (MeOD, 300 MHz): 8.65(2H, dd), 8.29 (1H, s), 8.25 (2H, dd), 7.41-7.35 (5H, m), 4.09 (1H, dd),3.86 (1H, s), 3.76-3.63 (2H, m), 3.00-2.97 (2H, d) 542 [336]

method: 5, RT: 2.98 min, MI: 400 [M + 1] 1H NMR (DMSO, 300 MHz): 8.66(2H, d), 8.54 (1H, s, br), 8.31 (2H, s), 8.04 (2H, d), 7.93 (1H, s),7.34 (5H, m), 6.73 (1H, t), 5.35 (2H, d), 3.80 (2H, m), 3.50 (2H, m),2.99 (1H, dd), 2.65 (1H, dd) 543 [BB-35]

method: 5, RT: 2.77 min, MI: 452 [M + 1] ^(c)Li-Mei Wei, Li-Lan Wei,Wen-Bin Pan and Ming-Jung Wu Tetrahedron Letters, 2003, vol. 44, p.595-597 ^(d)Emme, Ingo; Bruneau, Christian; Dixneuf, Pierre H.;Militzer, Hans-Christian; Meijere, Armin de; Synthesis, 2007, vol. 22 p.3574-358 ^(e)Dinges, Juergen; Albert, Daniel H.; Arnold, Lee D.;Ashworth, Kimba L.; Akritopoulou-Zanze, Irini; Bousquet, Peter F.;Bouska, Jennifer J.; Cunha, George A.; Davidsen, Steven K.; Diaz,Gilbert J.; Djuric, Stevan W.; et al. Journal of Medicinal Chemistry,2007, vol. 50, No. 9 p. 2011-2029 ^(f)Bradbury, Barton J.; Baumgold,Jesse; Jacobson, Kenneth A. Journal of Medicinal Chemistry, 1990, vol.33, No. 2 p. 741-748 ^(g)Derived from TBDMS protected acetylene.^(h)Derived from TMS protected acetylene.

General Synthesis of fluoro-alkynyl-7-4PT32P Derivatives of GeneralFormula [G-134], (Scheme B10)

The7-Bromo-6-substituted-4-amino-2-(3-substituted-pyridin-4-yl)-thieno[3,2-d]pyrimidinederivative of general formula [G-119] was involved in a Sonogashiracoupling reaction utilising a suitable terminal propargylic orhomopropargylic alcohol, of general formula [G-136], in the presence ofcopper(I)iodide with Pd(PPh₃)₂Cl₂ as catalyst, triphenylphosphine asligand, and a base such as Et₃N, or DEA in a polar solvent such as DMAor DMF at a high temperature either by heating thermally or using amicrowave reactor. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theintermediate was purified by column chromatography to give theacetylenic intermediate. This was involved in a fluorination reactionutilising (diethylamino)sulfur trifluoride in a chlorinated solvent suchas chloroform or DCM at low temperature. After reaction work up,typically by a liquid-liquid extraction, the N-Boc derivatives weredeprotected under acidic conditions with a strong acid such as TFA, HClin a solvent such as DCM, DCE or 1,4-dioxane or by catch and releasesulfonic acidic resins such as polymer supported toluene sulfonic acidand the crude reaction product was purified by reverse phase preparativeHPLC.

Synthesis of(S)—N*1*-[7-(3-Fluoro-but-1-ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine[544]

A microwave vial was charged with[(S)-1-Benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34](100 mg, 0.185 mmol), (S)-(−)-3-Butyn-2-ol(59 μL, 0.740 mmol), Bis(triphenylphosphine)palladiumchloride (13 mg,0.018 mmol), Copper(I)Iodide (4 mg, 0.019 mmol), triphenylphosphine (10mg, 0.036 mmol), diethylamine (0.28 ml, 2.686 mmol) and DMF (0.8 ml).The reaction mixture was heated under microwave irradiation then thecrude product isolated by liquid-liquid extraction and purified bycolumn chromatography (0-5% MeOH:DCM) to provide the desired propargylicalcohol which was dissolved in CHCl₃ (2 ml) and cooled to 0° C. DAST(100 μl, 0.82 mmol) was added and the mixture stirred for 2 hours at 0°C. The reaction mixture was quenched with ice, basified with NaHCO₃ andthe crude product extracted into DCM, then loaded onto a phaseseparation cartridge. The DCM solution was cooled to 0° C. and TFAadded. After 2 hours the reaction mixture was loaded onto an SCXcartridge and washed with MeOH then the product eluted with 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the crude product was purified by preparative HPLC(method A) to yield the title compound. LCMS method: 5, RT: 3.32 min,MI: 432 [M+1]. 1H NMR (DMSO, 300 MHz): 8.87 (1H, s, br), 8.67 (2H, d),8.50 (1H, s), 8.28 (2H, s), 7.99 (2H, d), 7.39-7.33 (5H, m), 5.75 (1H,dq), 3.97-3.92 (1H, m), 3.54-3.45 (2H, m), 2.93-2.77 (2H, m), 1.68 (3H,dd).

The following compounds were prepared according to the general synthesisshown in scheme B10:

Alkyne Ex SM [G-136] Characterisation 545 [BB- 34]

method: 5, RT: 2.97 min, MI: 418 [M + 1] 1H NMR (DMSO, 300 MHz): 8.68(2H, d), 8.60 (1H, s, br), 8.53 (1H, s), 8.28 (1H, s), 8.03 (2H, d),7.37-7.30 (5H, m), 5.52 (1H, s), 5.37 (1H, s), 3.47-3.39 (2H, m),2.91-2.75 (2H, m) 546 [BB- 34]

method: 5, RT: 2.93 min, MI: 432 [M + 1] 1H NMR (DMSO, 300 MHz): 8.68(2H, d), 8.32 (1H, s), 8.27 (1H, s), 8.03 (2H, d), 7.37-7.30 (5H, m),4.71 (1H, t), 4.56 (1H, t), 3.88 (1H, d, br), 3.46 (2H, m), 3.01 (1H,t), 2.93 (1H, t), 2.84-2.78 (2H, m)

Synthesis of 7(S)-3-Phenyl-N*1*-[2-pyridin-4-yl-7-(3H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-propane-1,2-diamine[547] (Scheme B11)

Synthesis of(S)-3-Phenyl-N*1*-[2-pyridin-4-yl-7-(3H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-propane-1,2-diamine[547]

A microwave vial was charged with[(S)-1-Benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34](60 mg, 0.114 mmol), (TMS)-acetylene (65μL, 0.456 mmol), Bis(triphenylphosphine)palladiumchloride (9 mg, 0.012mmol), copper (I) iodide (3 mg, 0.012 mmol), triphenylphosphine (7 mg,0.024 mmol), diethylamine (0.2 ml) and DMF (0.8 ml). The reactionmixture was heated under microwave irradiation then the crude productisolated by liquid-liquid extraction. To a stirred solution of the crudeacetylene and copper (I) iodide (2 mg, 0.006 mmol) in DMF (2 ml) wasadded TMS azide (30 μL, 0.226 mmol) and the reaction mixture heated to100° C. After 18 hours the reaction mixture was loaded onto an SCXcartridge and washed with MeOH then the product eluted with 2Mammonia/methanol and evaporated. The crude product was dissolved in DCM(2 ml) and TFA added (2 ml), and after 5 hours the reaction mixtureagain loaded onto an SCX cartridge and washed with MeOH then the producteluted with 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product was purifiedby preparative HPLC (method A) to yield the title compound. LCMS method:5, RT: 2.80 min, MI: 429 [M+1]. 1H NMR (DMSO, 300 MHz): 8.78 (1H, s),8.69 (2H, d), 8.53 (1H, s), 8.36 (1H, s, br), 8.10 (2H, d), 7.39-7.33(5H, m), 3.95 (1H, m), 3.51 (2H, m), 2.95-2.93 (1H, m), 2.74 (1H, m).

General Synthesis of aryl-ethynyl-7-substituted-4PT32P Derivatives ofGeneral Formula [G-138] (Scheme B12)

The 7-Bromo-4PT32P derivative, of general formula [G-119], was involvedin a Sonogashira coupling reaction utilising a protected acetylene, inthe presence of copper(I)iodide with Pd(PPh₃)₂Cl₂ as catalyst,triphenylphosphine as a ligand, and a base such as Et₃N, or DEA in apolar solvent such as DMA or DMF at a high temperature either by heatingthermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the protected acetylene was deprotected using asuitable source of fluoride such as TBAF, and then subjected to a secondSonogashira with the appropriate bromide, of general formula [G-137].After reaction work up, typically by a liquid-liquid extraction, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, HCl in a solvent such as DCM, DCE or 1,4-dioxane or bycatch and release sulfonic acidic resins such as polymer supportedtoluene sulfonic acid and the crude reaction product was purified byreverse phase preparative HPLC.

Synthesis of(S)-3-Phenyl-N*1*-(2-pyridin-4-yl-7-thiazol-4-ylethynyl-thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine[548]

A microwave vial was charged with[(S)-1-benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34](500 mg, 0.925 mmol),tert-butyldimethylsilylacetylene (700 μL, 3.7 mmol),bis(triphenylphosphine)palladiumchloride (65 mg, 0.093 mmol), copper (I)iodide (18 mg, 0.093 mmol), triphenylphosphine (50 mg, 0.186 mmol),diethylamine (0.2 ml) and DMF (0.8 ml). The reaction mixture was heatedunder microwave irradiation at 150° C. for 10 min then the crudereaction mixture was partitioned between (DCM:H₂O) and organic phaseseparated, dried (MgSO₄), filtered and evaporated under reducedpressure. The crude reaction product was dissolved in THF (15 ml),cooled to 0° C. and TBAF (1M in THF, 1.1 ml, 1.06 mmol) added. After 3hours the crude reaction mixture was partitioned between (DCM:H₂O) andorganic phase separated, dried (MgSO₄), filtered and evaporated underreduced pressure and used crude in the second Sonogashira coupling. Tothe crude reaction product (100 mg, 0.2 mmol) was added 4-bromothiazole(74 μl, 0.84 mmol), dichlorobis(triphenylphosphine)-palladium(II) (15mg, 0.021 mmol), PPh₃ (11 mg, 0.042 mmol), CuI (4 mg, 0.021 mmol) anddiethylamine-DMF (1:4, 1 ml) and then mixture was heated under microwaveirradiation at 150° C. for 10 min. The crude reaction mixture waspartitioned between (DCM:H₂O) and organic phase separated, dried(MgSO₄), filtered and evaporated under reduced pressure. The crudereaction product was dissolved in DCM (2 ml) and TFA (1 ml) was addedand the mixture was stirred at room temperature for 2 hours then thereaction mixture was loaded onto an SCX cartridge and washed with MeOHthen the product eluted with 2M ammonia/methanol. The ammonia/methanoleluent was concentrated under reduced pressure and the crude product waspurified by preparative HPLC (method A) to yield the title compound.LCMS method: 5, RT: 3.05 min, MI: 469 [M+1]. 1H NMR (MeOD, 300 MHz) 9.08(1H, d), 8.58 (2H, d), 8.28 (2H, d), 8.27 (1H, s), 8.00 (1H, d),7.36-7.24 (5H, m), 3.97 (1H, dd), 3.54-3.47 (2H, m), 2.84-2.81 (2H, m).

The following compounds were prepared according to the general synthesisshown in Scheme B12:

Arylhalide Ex SM [G-137] Characterisation 539 [BB- 34]

method: 5, RT: 3.03 min, MI: 452 [M + 1] 1H NMR (MeOD, 300 MHz): 8.61(2H, d), 8.44 (1H, s), 8.28 (1H, s), 8.23 (2H, d), 7.71 (1H, s),7.42-7.38 (5H, m), 6.63 (1H, s), 4.15 (1H, dd), 3.96-3.89 (1H,m), 3.73(1H, dd), 3.14-3.03 (2H, m).

General Synthesis of 7-amido substituted-4PT32P Derivatives of GeneralFormula [G-139] (Scheme B13)

The 7-bromo-4PT32P derivative, of general formula [G-119], was involvedin a carbonylation type reaction utilising a suitable amine, of generalformula [G-140], a carbonyl source such as molybdenum hexacarbonyl, apalladium catalyst such as cataCXium C, a ligand such astri-tert-butylphosphonium tetrafluoroborate and a base such as DBU in apolar solvent such as dioxane at high temperature either by heatingthermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release the crude reaction product was purified byreverse phase preparative HPLC

Synthesis of4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidine-7-carboxylicacid dimethylamide [550]

A microwave vial was charged with(S)—N*1*-(7-bromo-6-methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine [336](50 mg, 0.114mmol), dimethylamine (2M in THF, 570 μl, 1.14 mmol), CataCXium C (10 mg,0.010 mmol), tri-tert-butylphosphonium tetrafluoroborate (6 mg, 0.020mmol), DBU (51 μl, 0.342 mmol), molybdenum hexacarbonyl (30 mg, 0.114mmol) and dioxane (0.5 ml). The reaction was heated to 140° C. for 15minutes under microwave irradiation. The mixture was then loaded onto aSCX-2 cartridge and washed with methanol. The product was released fromthe cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method B) to yield thetitle compound. LCMS method: 5, RT: 2.28 min, MI: 433 [M+1]. 1H NMR (300MHz, DMSO): 8.68 (2H, d), 8.26 (2H, s), 8.04 (2H, d), 7.31 (5H, m), 3.81(1H, d, br), 3.33 (1H, m), 2.67 (3H, m), 1.29 (3H, s), 1.25 (3H, s).

The following compounds were prepared according to the general synthesisshown in Scheme B13:

Amine Ex SM [G-140] Characterisation 551 [336]

method: 8, RT: 3.59 min, MI: 447 [M + 1] 552 [336]

method: 8, RT: 2.80 min, MI: 461 [M + 1] 553 [336]

method: 6, RT: 5.12 min, MI: 419 [M + 1] 554 [336]

method: 5, RT: 3.32 min, MI: 433 [M + 1] 8 (d, 2H), 8.77 (s, 1H). 8.72(d, 2H), 8.2 (s, 1H), 7.33 (m, 5H), 3.91 (m, 2H), 3.48 (m, 2H), 3.42 (m,1H), 2.88 (m, 2H), 1.27 (t, 3H) 555 [336]

method: 5, RT: 3.64 min, MI: 447 [M + 1] 1H NMR (300 MHz, DMSO): 8.76(s, 1H)., 8.73 (d, 2H), 8.26 (s, 1H), 7.97 (d, 2H), 7.34 (m, 5H), 4.11(sep, 1H), 3.91 (m, 2H), 3.48 (m, 2H), 3.42 (m, 1H), 1.32 (d, 6H) 556[336]

method: 5, RT: 3.43 min, MI: 445 [M + 1] 1H NMR (300 MHz, DMSO): 8.72(d, 2H), 8.29 (s, 1H), 7.89 (d, 2H), 7.33 (m, 5H), 3.90 (m, 1H), 3.47(m, 2H), 2.95 (m, 2H), 2.76 (m, 1H), 0.85 (m, 2H), 0.65 (m, 2H) 557[336]

method: 5, RT: 3.95 min, MI: 461 [M + 1] 1H NMR (300 MHz, DMSO): 8.73(s, 1H). 8.70 (d, 2H), 8.27 (s, 1H), 7.99 (d, 2H), 7.31 (m, 5H), 3.86(m, 1H), 3.42 (m, 2H), 2.81 (m, 2H), 1.49 (s, 9H)

Synthesis of(E)-3-[4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-acrylicacid tert-butyl ester [558] (Scheme B14)

A microwave vial was charged with[(S)-1-Benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34](50 mg, 0.091 mmol), tert-butyl acrylate(271, 0.182 mmol), palladium acetate (2 mg, 0.009 mmol),tri-tert-butylphosphonium tetrafluoroborate (3 mg, 0.010 mmol), sodiumacetate (15 mg, 0.182 mmol) and DMF (1 ml). The reaction was heated to150° C. for 30 minutes under microwave irradiation. The mixture was thenloaded onto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was dissolved in DCM (2 ml) and TFA (1 ml) was added andthe mixture was stirred at room temperature for 1 hour. After completionthe mixture was loaded onto a SCX-2 cartridge and washed with methanol.The product was released from the cartridge using a solution of 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the crude product was purified by preparative HPLC(method B) to yield the title compound. LCMS method: 5, RT: 2.98 min,MI: 432 [M+1]. 1H NMR (300 MHz, DMSO): 8.84 (1H, s, br), 8.65 (2H, d),8.53 (1H, s), 7.94 (2H, d), 7.78 (1H, d, J=15 Hz), 7.34 (5H, m), 7.25(1H, d, J=15 Hz), 3.94 (1H, d, br), 3.62 (2H, m), 3.01 (1H, dd), 2.85(1H, m).

Synthesis of(7-Ethynyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine(559) (Scheme B15)

A microwave vial was charged with(7-Bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine[351] (70 mg, 0.186 mmol),2-[(tert-Butyl-dimethyl-silanyl)-ethynyl]boronic acid pinacol ester (100mg, 0.372 mmol), tetrakis (triphenyl phosphine) palladium (22 mg, 0.019mmol), Na₂CO₃ (2M in water, 200 μl, 0.4 mmol) and EtOH (1 ml). Thereaction was heated to 150° C. for 15 minutes under microwaveirradiation. The mixture was then loaded onto a SCX-2 cartridge andwashed with methanol. The product was released from the cartridge usinga solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product dissolved inTHF (2 ml), cooled to 0° C. and TBAF (190 μl, 1M in THF, 0.372 mmol)added. After 18 hours the reaction mixture was concentrated underreduced pressure and the crude reaction mixture was partitioned between(DCM:H₂O) and organic phase separated, dried (MgSO₄), filtered andevaporated under reduced pressure and the residue purified bypreparative HPLC (method B) to yield to the title compound. LCMS method:5, RT: 1.87 min, MI: 322 [M+1]. ¹H NMR (DMSO, 300 MHz): 8.59 (2H, d),8.52 (1H, s), 8.45 (2H, d), 4.93 (1H, dd), 4.48 (1H, s), 3.68 (1H, m),3.09 (1H, m), 2.49 (2H, m), 2.35 (1H, m), 2.16 (1H, m).

Synthesis of4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidine-7-carbonitrile(560) (Scheme B16)

A round bottomed flask was charged with[(S)-1-Benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34] (50 mg, 0.093 mmol), copper cyanide (25mg, 0.279 mmol) and DMA (2 ml). The reaction was heated to 150° C. for18 hours. The crude reaction mixture was partitioned between (DCM:H₂O)and organic phase separated, dried (MgSO₄), filtered and evaporatedunder reduced pressure to a volume of 2 ml. The mixture was cooled to 0°C. and TFA (2 ml) was added. After 18 hours the solution was loaded ontoa SCX-2 cartridge and washed with methanol. The product was releasedfrom the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method B) to yield tothe title compound. LCMS method: 5, RT: 2.75 min, MI: 387 [M+1].

Synthesis of (S)-3-Phenyl-N*1*-(7-pyrazol-1-yl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine (561) (Scheme B17)

A microwave vial was charged with(S)—N*1*-(7-Bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[336] (50 mg, 0.111 mmol), pyrazole (12 mg, 0.555 mmol), copper iodide(5 mg, 0.022 mmol), caesium carbonate (73 mg, 0.222 mmol) and DMF (1ml). The reaction was heated to 190° C. under microwave irradiation for5 minutes. The solution was then loaded onto a SCX-2 cartridge andwashed with methanol. The product was released from the cartridge usinga solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product was purifiedby preparative HPLC (method B) to yield to the title compound. LCMSmethod: 5, RT: 3.11 min, MI: 428 [M+1]. 1H NMR (DMSO) 8.71 (1H, d), 8.65(2H, d), 7.95 (2H, d), 7.84 (1H, s), 7.76 (1H, s), 7.38 (5H, m), 6.68(1H, t), 3.94 (1H, m), 3.57 (2H, m), 2.97 (1H, dd), 2.84 (1H, m).

Synthesis of(S)-3-Phenyl-N*1*-(2-pyridin-4-yl-7-[1,2,3]triazol-1-yl-thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine(562) (Scheme B18)

A microwave vial was charged with7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-20] (0.13 g, 0.42mmol), 1,2,3-triazole (56 mg, 0.811 mmol), copper iodide (6 mg, 0.033mmol), caesium carbonate (106 mg, 0.324 mmol) and DMF (1 ml). Thereaction was heated to 240° C. under microwave irradiation for 2 hours.The solution was then loaded onto a SCX-2 cartridge and washed withmethanol. The product was released from the cartridge using a solutionof 2M ammonia/methanol. The ammonia/methanol eluent was concentratedunder reduced pressure and the crude product suspended in POCl₃ andheated to reflux. After 1 hour the reaction mixture was cooled,concentrated and azeotroped with toluene twice. The residue was basifiedwith a 2M solution of NaOH and the product extracted into DCM (×2). Thecombined organics were dried (MgSO₄), filtered and evaporated underreduced pressure. The crude product was dissolved in DMA (2 ml) andtriethylamine (174 μl, 1.257 mmol) and (S)-3-Phenyl-propane-1,2-diamine(75 mg, 0.503 mmol) was added. After 18 hours the solution was loadedonto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product purified by preparative HPLC (method B) to yield to thetitle compound. LCMS method: 17, RT: 2.91 min, MI: 429 [M+1]. ¹H NMR(300 MHz, DMSO) 9.23 (1H, s), 8.70 (2H, d), 8.69 (1H, s), 8.07 (2H, d),8.04 (1H, s), 7.33 (5H, m), 3.92 (1H, m), 3.45 (2H, m), 2.82 (2H, m).

Synthesis of(S)—N*1*-[7-(2-Cyclopropyl-ethyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine(563) (Scheme B19)

A microwave vial was charged with(S)—N*1*-(7-Bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[336] (50 mg, 0.114 mmol), trans-2-cyclopropylvinylboronic acid pinacolester (44 mg, 0.228 mmol), tetrakis (triphenyl phosphine) palladium (13mg, 0.011 mmol), Na₂CO₃ (2M in water, 200 μl, 0.4 mmol) and EtOH (1 ml).The reaction was heated to 150° C. for 15 minutes under microwaveirradiation. The mixture was then loaded onto a SCX-2 cartridge andwashed with methanol. The product was released from the cartridge usinga solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product taken up inEtOH, Pd/C (5%, 10 mg) added followed by a few drops of formic acid andthe reaction mixture stirred under an atmosphere of hydrogen at 50° C.for 18 hours. The suspension was filtered through celite, concentratedunder reduced pressure and purified by preparative HPLC (method B) toyield to the title compound. LCMS method: 5, RT: 4.23 min, MI: 430[M+1]. ¹H NMR (DMSO, 300 MHz) 8.66 (2H, d), 8.41 (1H, s), 8.34 (1H, s),8.02 (2H, s), 7.79 (1H, d), 7.35 (5H, m), 3.92 (1H, m), 3.49 (2H, m),2.91 (4H, m), 1.63 (2H, m), 0.76 (1H, m), 0.40 (2H, m), 0.06 (2H, m).

Synthesis of(S)—N*1*-[7-Bromo-2-(1-oxy-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine(564) (Scheme B20)

To a stirred suspension of[(S)-1-benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34](100 mg, 0.185 mmol), in DCM (2 ml) at 0°C. was added mCPBA (35 mg, 0.204 mmol). After 18 hours the reactiondiluted with DCM (10 ml) and the mixture washed with saturated solutionof Na₂SO₃ (2×10 ml) then H₂O (10 ml) and finally brine (10 ml), dried(MgSO₄), filtered and evaporated under reduced pressure and the crudeproduct was purified by column chromatography (0-5% MeOH:DCM) to providethe desired reaction intermediate. This was taken up in 4N HCl indioxane (2 ml) and stirred at room temperature for 2 hours. The crudereaction mixture was loaded onto a SCX-2 cartridge and washed withmethanol. The product was released from the cartridge using a solutionof 2M ammonia/methanol. The ammonia/methanol eluent was concentratedunder reduced pressure and the crude product was purified by preparativeHPLC (method B) to yield to the title compound. LCMS method: 5, RT: 2.81min, MI: 456-458 [M+1]. H NMR (MeOD, 300 MHz) 8.53 (1H, s), 8.31 (q,4H), 8.10 (1H, s), 7.38-7.31 (5H, m), 4.06-4.03 (1H, m), 3.64-3.60 (1H,m), 3.31-3.29 (1H, m), 2.93 (2H, m).

Synthesis of(S)—N*1*-[2-(1-Oxy-pyridin-4-yl)-7-(2H-pyrazol-3-yl)-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine(565) (Scheme B21)

To a stirred suspension of[(S)-1-benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34](200 mg, 0.37 mmol), in DCM (2 ml) at 0° C.was added mCPBA (70 mg, 0.408 mmol). After 18 hours the reaction wasdiluted with DCM (10 ml) and the mixture washed with saturated solutionof Na₂SO₃ (2×10 ml) then H₂O (10 ml) and finally brine (10 ml), dried(MgSO₄), filtered and evaporated under reduced pressure. To the crudereaction product was added 1H-Pyrazole-5-boronic acid (50 mg, 0.444mmol), Pd(PPh₃)₄ (43 mg, 0.037 mmol), Na₂CO₃ (2M in water, 200 μl, 0.4mmol) and EtOH (2 ml) and the mixture was heated to 150° C. for 15minutes under microwave irradiation. The mixture was then loaded onto aSCX-2 cartridge and washed with methanol. The product was released fromthe cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure. Thiswas suspended in 4N HCl:dioxine (2 ml) and stirred at room temperaturefor 18 hours. The reaction mixture was evaporated under reduced pressureand the residue dissolved in MeOH, loaded onto a SCX-2 cartridge andwashed with methanol. The product was released from the cartridge usinga solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product was purifiedby preparative HPLC (method B) to yield to the title compound. LCMSmethod: 5, RT: 3.08 min, MI: 444 [M+1]. ¹H NMR (DMSO, 300 MHz) 8.38 (1H,s, br), 8.23 (2H, d), 8.07 (2H, d), 7.83 (1H, s), 7.35-7.29 (6H, m),3.87 (1H, m), 3.48-3.45 (2H, m), 2.90-2.83 (2H, m).

General Synthesis of 7-amino-substituted 4PT32P derivatives of GeneralFormula [G-143] (Scheme B22)

2-Pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol, of general formula [G-141],was involved in a chlorination reaction using phosphorus oxychloride,then nitrated at the 7-position using a combination of fuming nitricacid and concentrated sulphuric acid, to give compounds of generalformula [G-142]. The nitro group was subsequently reduced under adissolving metal reduction using iron and hydrochloric acid, and finallyreacted with an N-Boc protected primary or secondary amine derivative,of general formula [G-117], in a polar aprotic solvent such as DMA, DMF,NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMMat ambient temperature. After reaction work up, typically by aliquid-liquid extraction, the N-Boc derivatives were deprotected underacidic conditions with a strong acid such as TFA, HCl in a solvent suchas DCM, DCE or 1,4-dioxane or by catch and release sulfonic acidicresins such as polymer supported toluene sulfonic acid and the crudereaction product was purified by reverse phase preparative HPLC.

Synthesis of 4-Chloro-7-nitro-2-pyridin-4-yl-thieno[3,2-d]pyrimidine[BB-44]

2-Pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ol [BB-20] (5 g, 21.8 mmol) washeated to 80° C. in phosphorus oxychloride (50 ml) for 30 minutes. Thereaction mixture was allowed to cool to room temperature then evaporatedunder reduced pressure and the crude product was zeotroped with toluene.The residue was trituration with a mixture of diethyl ether and 2N NaOHand the solid formed was was collected by filtration and washed withwater followed by ether to yield the title compound as a beige solidwhich was used in the next step without further purification: LCMSmethod: 17, RT: 4.91 min, MI: 248 [M+1].

To a solution of 4-Chloro-2-pyridin-4-yl-thieno[3,2-d]pyrimidine (4 g,15.9 mmol) in sulphuric acid (10 ml) was added nitric acid (1 ml) andthe reaction mixture heated to 40° C. After 2 hours the solution wascooled to 0° C. then added to vigorously stirred ice-water, and theresulting precipitate was collected by filtration and washed with waterto yield the title compound as a yellow solid which was used in the nextstep without further purification: LCMS method: 5, RT: 4.54 min, MI: 293[M+1]. 1H NMR (DMSO, 300 MHz) 9.83 (1H, s), 9.01 (2H, d), 8.65 (2H, d).

Synthesis ofN*4*-((S)-2-Amino-3-phenyl-propyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidine-4,7-diamine[566]

To a stirred suspension of4-chloro-7-nitro-2-pyridin-4-yl-thieno[3,2-d]pyrimidine [BB-44] (1 g,3.42 mmol) and iron powder (770 mg, 13.7 mmol) in EtOH (20 ml) at 40° C.was added concentrated HCl (20 ml) dropwise. After 20 minutes thereaction mixture was loaded onto a SCX-2 cartridge and washed withmethanol. The product was released from the cartridge using a solutionof 2M ammonia/methanol. The ammonia/methanol eluent was concentratedunder reduced pressure to give a brown solid. LCMS method: 18, RT: 3.38min, MI: 263 [M+1].

To a solution of 4-Chloro-7-amino-2-pyridin-4-yl-thieno[3,2-d]pyrimidine(130 mg, 0.476 mmol) in DMA (1 ml) was added((S)-2-Amino-1-benzyl-ethyl)-carbamic acid tert-butyl ester (143 mg,0.571 mmol) followed by triethylamine (200 μl, 1.43 mmol), and themixture stirred at room temperature for 18 hours. The crude reactionmixture was partitioned between (DCM:H₂O) and organic phase separated,dried (MgSO₄), filtered and evaporated under reduced pressure and thecrude product was loaded onto a phase separation cartridge and washedwith methanol. The product was released from the cartridge using asolution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure to give a brown solid. The crudereaction product was dissolved in DCM (2 ml) and TFA (2 ml) was addedand the mixture was stirred at room temperature for 1 hour then themixture was loaded onto a SCX-2 cartridge and washed with methanol. Theproduct was released from the cartridge using a solution of 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the crude product was purified by preparative HPLC(method A) to yield the title compound. LCMS method: 6, RT: 4.62 min,MI: 377 [M+1]. ¹H NMR (DMSO) 8.67 (2H, d), 8.16 (2H, d), 7.92 (1H, s),7.28 (5H, m), 6.49 (1H, s), 5.29 (2H, s, br), 3.79 (1H, m), 3.28 (2H,m), 2.69 (2H, m).

The following compounds were prepared according to the general synthesisshown in Scheme B22:

Amine Example SM [G-117] Characterisation 567 [BB-44]

method: 6, RT: 3.90 min, MI: 313 [M + 1]

General Synthesis of 7-heteroaryl-substituted 4PT32P Derivatives ofGeneral Formula [G-145] (Scheme B23)

The 7-bromo-substituted 4PT32P derivative, of general formula [G-119],was involved in a Heck type reaction utilising a suitable olefin, ofgeneral formula [G-146], a palladium catalyst such as palladium acetate,a ligand such as tri-t-butyl phosphonium tetrafluoroborate and a basesuch as sodium acetate in a polar solvent such as DMF at hightemperature either by heating thermally or using a microwave reactor.The generated olefin derivative, of general formula [G-144], was thencyclised using either para-toluenesulfonylhydrazide orN-hydroxyl-4-toluenesulfonamide to provide either the correspondingpyrazole or isoxazole respectively. After reaction work up, typically bya liquid-liquid extraction, the N-Boc derivatives were deprotected underacidic conditions with a strong acid such as TFA, HCl in a solvent suchas DCM, DCE or 1,4-dioxane or by catch and release sulfonic acidicresins such as polymer supported toluene sulfonic acid and the crudereaction product was purified by reverse phase preparative HPLC

Synthesis of(E)-3-[4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-acrylicacid tert-butyl ester [BB-45]

A microwave vial was charged with[(S)-1-Benzyl-2-(7-bromo-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [BB-34](50 mg, 0.091 mmol), tert-butyl acrylate(27 μl, 0.182 mmol), palladium acetate (2 mg, 0.009 mmol),tri-tert-butylphosphonium tetrafluoroborate (3 mg, 0.010 mmol), sodiumacetate (15 mg, 0.182 mmol) and DMF (1 ml). The reaction was heated to150° C. for 30 minutes under microwave irradiation. The mixture was thenloaded onto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was purified by preparative HPLC (method B) to yield thetitle compound. LCMS method: 5, RT: 2.98 min, MI: 432 [M+1]. ¹H NMR (300MHz, DMSO): 8.84 (1H, s, br), 8.65 (2H, d), 8.53 (1H, s), 7.94 (2H, d),7.78 (1H, d, J=15 Hz), 7.34 (5H, m), 7.25 (1H, d, J=15 Hz), 3.94 (1H, d,br), 3.62 (2H, m), 3.01 (1H, dd), 2.85 (1H, m).

Synthesis of(S)—N*1*-[7-(5-Methyl-isoxazol-3-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine[568]

N-hydroxyl-4-toluenesulfonamide (128 mg, 0.74 mmol) was added to astirred suspension of(E)-3-[4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-acrylicacid tert-butyl ester [BB-45] (90 mg, 0.166 mmol) in ethanol (2 ml) andthe reaction mixture heated to 90° C. After 2 hours the mixture wasloaded onto a SCX-2 cartridge and washed with methanol. The product wasreleased from the cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure and thecrude product was dissolved in DCM (2 ml) and TFA (2 ml) was added andthe mixture stirred at room temperature for 1 hour. After completion themixture was loaded onto a SCX-2 cartridge and washed with methanol. Theproduct was released from the cartridge using a solution of 2Mammonia/methanol. The ammonia/methanol eluent was concentrated underreduced pressure and the crude product was purified by preparative HPLC(method B) to yield the title compound. LCMS method: 5, RT: 3.36 min,MI: 443 [M+1]. ¹H NMR (300 MHz, DMSO): 8.70 (2H, d), 8.66 (1H, s), 8.50(1H, s, br), 8.11 (2H, d), 7.33 (5H, m), 7.24 (1H, s), 3.89 (1H, m),3.39 (2H, m), 2.77 (2H, m), 2.55 (3H, s).

The following compounds were prepared according to the general synthesisshown in Scheme B23:

Olefin Ex SM [G-146] Reactant Characterisation 569 [BB-34]

para- toluenesulfonylhydrazide method: 5, RT: 3.33 min, MI: 442 [M + 1]570 [BB-34]

N-hydroxyl-4- toluenesulfonamide method: 5, RT: 3.65 min, MI: 457 [M +1] 571 [BB-34]

para- toluenesulfonylhydrazide method: 6, RT: 6.00 min, MI: 456 [M + 1]1H NMR (300 MHz, DMSO): 8.71 (2H, d), 8.35 (1H, s), 8.26 (1H, s, br),8.11 (2H, d), 7.38-7.29 (5H, m), 7.09 (1H, s), 3.89 (1H, m), 2.82 (2H,m), 2.69 (2H, q), 1.27 (3H, t). 572 [BB-34]

N-hydroxyl-4- toluenesulfonamide method: 5, RT: 3.02 min, MI: 429 [M +1]

General Synthesis of 2-Amino-pyridyl-substituted-4PT32P Derivatives ofGeneral Formula [G-148], [G-149], [G-150] & [G-151] (Scheme B24)

The 2-chloropyridyl 4PT32P derivative of general formula [G-147] wasinvolved in a Buchwald type reaction utilising a suitable amine, ofgeneral formula [G-133], a palladium catalyst such as Pd(dba)₂ orPd(OAc)₂, a ligand such as Xantphos and a base such as NaOtBu or Cs₂CO₃in a polar solvent such as dioxane or a combination of dioxane and DMAat high temperature either by heating thermally or using a microwavereactor, to yield aminopyridyl 4PT32P derivative of general formula[G-148], method A. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theintermediate was purified by column chromatography and the N-Bocderivatives were deprotected under acidic conditions with a strong acidsuch as TFA, HCl in a solvent such as DCM, DCE or 1,4-dioxane or bycatch and release sulfonic acidic resins such as polymer supportedtoluene sulfonic acid and the crude reaction product was purified byreverse phase preparative HPLC. The 2-chloropyridyl 4PT32P derivative ofgeneral formula [G-147] was involved in a Buchwald type reactionutilising a suitable amide, of general formula [G-152], a palladiumcatalyst such as Pd(dba)₂ or Pd(OAc)₂, a ligand such as Xantphos and abase such as NaOtBu or Cs₂CO₃ in a polar solvent such as dioxane or acombination of dioxane and DMA at high temperature either by heatingthermally or using a microwave reactor, to yield aminopyridyl 4PT32Pderivative of general formula [G-149], method B. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the intermediate was purified by columnchromatography and the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, HCl in a solvent such as DCM,DCE or 1,4-dioxane or by catch and release sulfonic acidic resins suchas polymer supported toluene sulfonic acid and the crude reactionproduct was purified by reverse phase preparative HPLC. The2-chloropyridyl 4PT32P derivative of general formula [G-147] wasinvolved in a Buchwald type reaction utilising a suitable urea, ofgeneral formula [G-153], a palladium catalyst such as Pd(dba)₂ orPd(OAc)₂, a ligand such as2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and a base suchas NaOtBu or Cs₂CO₃ in a polar solvent such as dioxane or a combinationof dioxane and DMA at high temperature either by heating thermally orusing a microwave reactor, to yield aminopyridyl 4PT32P derivative ofgeneral formula [G-150], method C. After reaction work up, typically bya liquid-liquid extraction or purification by acidic ion exchangecatch-release, the intermediate was purified by column chromatographyand the N-Boc derivatives were deprotected under acidic conditions witha strong acid such as TFA, HCl in a solvent such as DCM, DCE or1,4-dioxane or by catch and release sulfonic acidic resins such aspolymer supported toluene sulfonic acid and the crude reaction productwas purified by reverse phase preparative HPLC. The 2-chloropyridyl4PT32P derivative of general formula [G-147] was involved in a Buchwaldtype reaction utilising a suitable sulfonamide, of general formula[G-154], a palladium catalyst such as Pd(dba)₂ or Pd(OAc)₂, a ligandsuch as 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and abase such as NaOtBu or Cs₂CO₃ in a polar solvent such as dioxane or acombination of dioxane and DMA at high temperature either by heatingthermally or using a microwave reactor, to yield aminopyridyl 4PT32Pderivative of general formula [G-151], method D. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the intermediate was purified by columnchromatography and the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, HCl in a solvent such as DCM,DCE or 1,4-dioxane or by catch and release sulfonic acidic resins suchas polymer supported toluene sulfonic acid and the crude reactionproduct was purified by reverse phase preparative HPLC.

Method A Synthesis of[2-(2-Phenylamino-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[573]

A microwave vial was charged with(R)-3-[2-(2-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-32] (50 mg, 0.116 mmol), Aniline (22 μl, 0.232mmol), Pd(dba)₂ (4 mg, 0.006 mmol), Xantphos (7 mg, 0.012 mmol), NaOtBu(23 mg, 0.232 mmol), DMA (few drops) and dioxane (1 ml). The reactionwas heated to 150° C. for 15 minutes under microwave irradiation. Thereaction mixture was partitioned between DCM and saturated NH₄Cl (50%)and the organic phase separated, dried (MgSO₄), filtered and evaporatedunder reduced pressure. The crude reaction product was dissolved in DCM(2 ml) and TFA (2 ml) was added and the mixture stirred at roomtemperature for 2 hours. The reaction mixture was loaded onto a SCX-2cartridge and washed with methanol. The product was released from thecartridge using a solution of 2M ammonia/methanol. The ammonia/methanoleluent was concentrated under reduced pressure and the crude product waspurified by preparative HPLC (method B) to yield the title compound.LCMS method: 5, RT: 2.16 min, MI: 389 [M+1]. ¹H NMR (300 MHz, DMSO):9.40 (1H, s), 8.40 (1H, d), 8.36 (1H, s), 8.27 (1H, d), 8.20 (1H, d),7.94 (1H, s), 7.74 (2H, d), 7.67 (1H, d), 7.48 (1H, d), 7.27 (2H, t),6.88 (1H, t), 4.94-4.85 (1H, m), 3.66 (1H, dd), 3.39-3.19 (3H, m),2.34-2.30 (1H, m), 2.17-2.10 (1H, m).

Method B Synthesis of Furan-2-carboxylic acid{4-[4-((R)-pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-yl)}-amide[574]

A microwave vial was charged with(R)-3-[2-(2-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-32] (50 mg, 0.11 mmol), furan-2-carboxamide(mg, 0.23 mmol), Pd(dba)₂ (4 mg, 0.006 mmol), Xantphos (7 mg, 0.012mmol), NaOtBu (23 mg, 0.23 mmol), DMA (few drops) and dioxane (1 ml).The reaction was heated to 150° C. for 15 minutes under microwaveirradiation. The reaction mixture was partitioned between DCM andsaturated NH₄Cl (50%) and the organic phase separated, dried (MgSO₄),filtered and evaporated under reduced pressure. The crude reactionproduct was dissolved in DCM (2 ml) and TFA (2 ml) was added and themixture stirred at 0° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure and the resulting residue wasdissolved in 10% HCOOH:MeOH and loaded onto an SCX cartridge which waswashed with MeOH and the product was released from the cartridge using asolution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure. The crude product was purified bypreparative HPLC (method B) to yield the title compound. LCMS method: 5,RT: 3.04 min, MI: 407 [M+1]. ¹H NMR (DMSO) 9.86 (1H, s), 9.09 (1H, s),8.44 (1H, d), 8.29 (1H, s), 8.21 (1H, d), 8.06 (1H, dd), 7.53 (1H, d),4.88 (1H, m), 4.52 (1H, dd), 4.04-3.97 (1H, m), 3.88-3.82 (1H, m), 3.52(1H, dd), 3.29-3.15 (3H, m), 2.34-1.89 (4H, m).

Method C Synthesis of1-Phenyl-3-{4-[4-((R)-pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-yl}-urea[575]

A microwave vial was charged with(R)-3-[2-(2-chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-32] (100 mg, 0.23 mmol), N-phenylurea (38 mg,0.278 mmol), Pd(dba)₂ (11 mg, 0.012 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg, 0.023mmol), Cs₂CO₃ (106 mg, 0.32 mmol), DMA (few drops) and dioxane (0.5 ml).The reaction was heated to 180° C. for 10 minutes under microwaveirradiation. The reaction mixture was partitioned between DCM and NH₄Cl(50%) and the organic phase collected then loaded onto a SCX-2 cartridgeand washed with methanol. The product was released from the cartridgeusing a solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product dissolved 4NHCl:dioxane (2 ml) and stirred at room temperature for 4 hr. Thereaction mixture was concentrated under reduced pressure and theresulting residue was dissolved in 10% HCOOH:MeOH and loaded onto an SCXcartridge which was washed with MeOH and the product was released fromthe cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure. Thecrude product was purified by preparative HPLC (method B) to yield thetitle compound. LCMS method: 5, RT: 3.05 min, MI: 432 [M+1]. ¹H NMR(MeOD) 8.46 (1H, s), 8.39 (1H, d), 8.36 (1H, s), 8.07 (1H, d), 7.96 (1H,dd), 7.53 (2H, dd), 7.49 (1H, d), 7.33 (2H, t), 7.08 (1H, t), 5.04 (1H,m), 3.87 (1H, d), 3.63-3.45 (3H, m), 2.58-2.49 (1H, m), 2.40-2.29 (1H,m).

Method D Synthesis ofN-({4-[4-((R)-Pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide[576]

A microwave vial was charged with(R)-3-[2-(2-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [BB-32] (100 mg, 0.23 mmol), benzenesulfonamide(44 mg, 0.278 mmol), Pd(dba)₂ (11 mg, 0.012 mmol),2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg, 0.023mmol), Cs₂CO₃ (106 mg, 0.32 mmol), DMA (few drops) and dioxane (0.5 ml).The reaction was heated to 180° C. for 10 minutes under microwaveirradiation. The reaction mixture was partitioned between DCM and NH₄Cl(50%) and the organic phase collected then loaded onto a SCX-2 cartridgeand washed with methanol. The product was released from the cartridgeusing a solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product dissolved 4NHCl:dioxane (2 ml) and stirred at room temperature for 4 hr. Thereaction mixture was concentrated under reduced pressure and theresulting residue was dissolved in 10% HCOOH:MeOH and loaded onto an SCXcartridge which was washed with MeOH and the product was released fromthe cartridge using a solution of 2M ammonia/methanol. Theammonia/methanol eluent was concentrated under reduced pressure. Thecrude product was purified by preparative HPLC (method B) to yield thetitle compound. LCMS method: 5, RT: 2.74 min, MI: 453 [M+1]. 1H NMR(DMSO) 8.41 (1H, d), 8.21 (1H, s), 8.10 (1H, d), 7.92-7.89 (2H, m), 7.75(1H, dd), 7.55-7.50 (5H, m), 4.85-4.80 (1H, m), 3.60 (1H, dd), 3.43-3.25(3H, m), 2.38-2.31 (1H, m), 2.19-2.11 (1H, m).

The following compounds were prepared according to the general synthesisshown in Scheme B24:

Exam- ple Method SM Amine Characterisation 577 A [BB-32]

method: 5, RT: 1.85 min, MI: 391 [M + 1] 578 B [BB-32]

method: 5, RT: 2.78 min, MI: 411 [M + 1] 1H NMR (DMSO, 300 MHz): 9.15(1H, s), 8.49 (2H, d), 8.30 (1H, s), 8.20 (1H, d), 8.07 (1H, d), 7.97(1H, s), 7.64 (1H, d), 7.54 (1H, d), 6.71 (1H, dd), 4.90-4.88 (1H, m),3.55 (1H, dd), 3.31- 3.15 (3H, m), 2.37-2.30 (1H, m), 2.15 (1H, m) 579 A[BB-31]

method: 5, RT: 2.81 min, MI: 407 [M + 1] 1H NMR (MeOD, 300 MHz): 8.32(2H, s), 8.11 (1H, d), 8.08 (1H, d), 7.53 (2H, dd), 7.45 (1H, d), 7.40(1H, d), 7.27 (2H, t), 6.95 (1H, t), 4.90 (1H, m), 3.73 (1H, dd),3.56-3.29 (3H, m), 2.51-2.44 (1H, m), 2.32-2.30 (1H, m). 580 A [BB-31]

method: 5, RT: 4.37 min, MI: 409 [M + 1] 1H NMR (MeOD, 300 MHz): 8.85(1H, d), 8.40 (1H, d), 8.29 (1H, d), 8.23 (1H, dd), 8.11 (1H, d), 8.02(1H, d), 7.91-7.88 (3H, m), 7.68 (1H, d), 7.50 (1H, d), 4.93-4.87 (1H,m), 3.78 (1H, dd), 3.62- 3.43 (3H, m), 2.56-2.45 (1H, m), 2.40-2.30 (1H,m) 581 C [BB-32]

method: 7, RT: 1.90 min, MI: 384 [M + 1] 1H NMR (MeOD, 300 MHz): 8.84(1H, s), 8.31 (1H, d), 7.99 (1H, d), 7.95 (1H, dd), 7.43 (1H, d),4.92-4.89 (1H, m), 3.54 (1H, dd), 3.23-3.20 (1H, m), 3.15-3.10 (2H, m),3.08 (6H, s), 2.41-2.37 (1H, m), 2.09-2.02 (1H, m). 582 C [BB-32]

method: 7, RT: 3.40 min, MI: 412 [M + 1] 1H NMR (MeOD, 300 MHz): 8.25(1H, d), 8.06 (1H, s), 8.00 (1H, d), 7.84 (1H, dd), 7.42 (1H, d),4.93-4.89 (1H, m), 3.51 (1H, Cdd), 3.18- 3.09 (2H, m), 2.41-2.37 (1H,m), 2.07-2.05 (1H, m), 1.43 (9H, s). 583 C [BB-32]

method: 7, RT: 2.26 min, MI: 370 [M + 1] 1H NMR (MeOD, 300 MHz): 8.27(1H, d), 8.04 (1H, s), 7.99 (1H, d), 7.85 (1H, dd), 7.43 (1H, d),4.93-4.89 (1H, m), 3.48 (1H, dd), 3.26-3.22 (1H, m), 3.12-3.08 (1H, m),3.04 (1H, dd), 2.90 (3H, s), 2.41-2.34 (1H, m), 2.06-1.99 (1H, m). 584 C[BB-32]

method: 7, RT: 2.48 min, MI: 424 [M + 1] 1H NMR (DMSO, 300 MHz): 9.15(1H, s), 8.75 (1H, s), 8.32 (1H, d), 8.19 (1H, d), 7.89 (1H, d), 7.51(1H, d), 4.79-4.75 (1H, m), 3.45-3.44 (2H, m), 3.21 (1H, dd), 3.07- 3.02(4H, m), 2.31-2.21 (1H, m), 2.02-1.97 (1H, m), 1.60- 1.50 (2H, m),1.49-1.41 (4H, m), 1.40-1.35 (2H, m). 585 A [BB-39b]

method: 5, RT: 2.41 min, MI: 409 [M + 1] 1H NMR (MeOD, 300 MHz): 9.52(1H, d), 8.49 (1H, s), 8.30 (1H, dd), 8.20 (1H, d), 8.16 (1H, d), 8.10(1H, d), 7.54 (1H, t), 7.47 (1H, d), 4.95-4.88 (1H, m), 3.76 (1H, dd),3.61-3.50 (3H, m), 2.53- 2.46 (1H, m), 2.36-2.31 (1H, m). 586 A [BB-32]

method: 6, RT: 5.68 min, MI: 417 [M + 1] 1H NMR (DMSO, 300 MHz): 8,39(d, 1H). 8.14 (d, 1H), 8 (d, 1H), 7.56 (s, 1H), 7.45 (m, 1H), 7.43 (m,1H), 7.31 (m, 2H), 7.16 (m, 1H), 5.07 (m, 1H), 4.82 (m, 1H), 3.24 (m,1H), 3.12 (m, 2H), 2.24 (m, 1H), 2.03 (m, 1H), 1.43 (d, 3H) 587 H

method: 6, RT: 5.7 min, MI: 417 [M + 1] 588 A [BB-32]

method: 6, RT: 5.22 min, MI: 405 [M + 1] 1H NMR (DMSO, 300 MHz): 8.46(m, 1H). 8.33 (m, 1H), 8.03 (s, 1H), 7.81 (m, 1H), 7.53 (m, 1H), 7.47(m, 1H), 7.44 (m, 1H), 4.85 (m, 1H), 3.66 (m, 1H), 3.18 (m, 1H), 3.15(m, 2H), 2.31 (m, 1H), 2.09 (m, 1H) 589 A [BB-32]

method: 6, RT: 5.93 min, MI: 431 [M + 1] 1H NMR (DMSO, 300 MHz): 8.31(d, 1H). 8.15 (d, 1H)., 7.98 (d, 1H), 7.57 (s, 1H), 7.44 (M, 1H), 7.36(m, 2H), 7.28 (m, 2H), 7.16 (m, 1H), 4.83 (m, 1H), 3.51 (m, 1H), 3.25(m, 2H), 3.10 (m, 2H), 2.26 (m, 1H), 2.04 (m, 1H), 1.76 (q, 2H), 0.90(t, 3H) 590 A [BB-32]

method: 6, RT: 5.95 min, MI: 431 [M + 1] 591 A [BB-32]

592 A [BB-32]

593 A [BB-32]

method: 6, RT: 5.49 min, MI: 433 [M + 1] 594 A [BB-32]

method: 5, RT: 1.8 min, MI: 353 [M + 1] 595 B [BB-32]

method: 5, RT: 5.41 min, MI: 423 [M + 1] 596 B [BB-32]

method: 5, RT: 5.61 min, MI: 447 [M + 1] 597 A [BB-32]

method: 10, RT: 1.61 min, MI: 367 [M + 1], 598 A [BB-32]

method: 10, RT: 1.82 min, MI: 403 [M + 1], 599 B [BB-32]

method: 10, RT: 1.52 min, MI: 381 [M + 1], 600 A [BB-32]

method: 10, RT: 1.53 min, MI: 390 [M + 1], 601 A [BB-32]

method: 10, RT: 2.26 min, MI: 466 [M + 1], 602 A [BB-32]

method: 10, RT: 1.39 min, MI: 475 [M + 1], 603 A [BB-32]

method: 10, RT: 1.28 min, MI: 488 [M + 1], 604 A [BB-32]

method: 10, RT: 1.71 min, MI: 415 [M + 1], 605 A [BB-32]

method: 10, RT: 1.44 min, MI: 487 [M + 1], 606 A [BB-32]

method: 10, RT: 1.76 min, MI: 414 [M + 1], 607 A [BB-32]

method: 10, RT: 1.86 min, MI: 414 [M + 1], 608 A [BB-32]

method: 10, RT: 1.45 min, MI: 472 [M + 1], 609 A [BB-32]

method: 10, RT: 1.71 min, MI: 415 [M + 1], 610 A [BB-32]

method: 10, RT: 1.89 min, MI: 496 [M + 1], 611 A [BB-32]

method: 10, RT: 1.39 min, MI: 472 [M + 1], 612 A [BB-32]

method: 10, RT: 1.85 min, MI: 496 [M + 1], 613 A [BB-32]

method: 10, RT: 1.35 min, MI: 529 [M + 1], 614 A [BB-32]

method: 10, RT: 1.35 min, MI: 469 [M + 1], 615 B [BB-32]

method: 10, RT: 1.60 min, MI: 419 [M + 1], 616 A [BB-32]

method: 10, RT: 2.28 min, MI: 471 [M + 1], 617 A [BB-32]

method: 10, RT: 2.33 min, MI: 471 [M + 1], 618 A [BB-32]

method: 10, RT: 1.90 min, MI: 435 [M + 1], 619 A [BB-39b]

method: 5, RT: 3.05 min, MI: 407 [M + 1] 1H NMR (MeOD) 8.10 (1H, d),7.99 (1H, d), 7.67 (2H, dd), 7.47 (1H, d), 7.33-7.24 (3H, m), 7.01 (1H,t), 4.95- 4.89 (1H, m), 3.76 (1H, dd), 3.64-3.55 (1H, m), 3.50- 3.40(1H, m), 2.53-2.44 (1H, m), 2.37-2.31 (1H, m). 620 B [BB-32]

method: 10, RT: 1.49 min, MI: 515 [M + 1], 621 B [BB-32]

method: 10, RT: 1.93 min, MI: 502 [M + 1], 622 D [BB-32]

method: 7, RT: 2.28 min, MI: 417 [M + 1] 1H NMR (MeOD) 8.38 (1H, s),8.17 (1H, d), 8.07 (1H, d), 7.90 (1H, dd), 7.48 (1H, d), 4.99-4.97 (1H,m), 3.86 (1H, dd), 3.62-3.56 (1H, m), 3.50- 3.46 (2H, m), 2.89-2.86 (1H,m), 2.58-2.51 (1H, m), 2.37- 2.32 (1H, m), 1.19-1.16 (2H, m), 1.03-0.99(2H, m). 623 A [BB-32]

method: 7, RT: 2.21 min, MI: 395 [M + 1] 1H NMR (MeOD) 7.99 (2H, d),7.48 (1H, s), 7.41 (2H, d), 4.92-4.89 (1H, m), 3.70-3.65 (1H, m), 3.52(1H, dd), 3.31- 3.29 (1H, m), 3.20-3.13 (2H, m), 2.40-2.36 (1H, m),2.09- 2.04 (3H, m), 1.81-1.78 (2H, m), 1.68-1.66 (1H, m), 1.48- 1.41(2H, m), 1.30-1.26 (3H, m). 624 D [BB-32]

method: 7, RT: 2.07 min, MI: 391 [M + 1] 1H NMR (MeOD) 8.29 (1H, s),8.19 (1H, d), 8.07 (1H, d), 7.90 (1H, d), 7.49 (1H, d), 5.01-4.95 (1H,m), 3.86 (1H, dd), 3.63-3.57 (1H, m), 3.52- 3.47 (2H, m), 3.20 (3H, s),2.59-2.51 (1H, m), 2.38-2.32 (1H, m). 625 A [BB-32]

method: 7, RT: 1.60 min, MI: 397 [M + 1] 1H NMR (MeOD) 8.03 (1H, d),8.00 (1H, d), 7.52 (1H, s), 7.45 (1H, dd), 7.42 (1H, d), 4.96-4.94 (1H,m), 4.00- 3.94 (3H, m), 3.65-3.55 (3H, m), 3.40-3.34 (2H, m), 3.29- 3.19(1H, m), 2.45-2.38 (1H, m), 2.16-2.13 (1H, m), 2.03- 2.00 (2H, m),1.61-1.54 (2H, m). 626 A [BB-32]

method: 5, RT: 1.87 min, MI: 355 [M + 1] 627

H

method: 10, RT: 1.67 min, MI: 440 [M + 1], 628

H

Method: 10, RT: 1.84 min, MI: 437 [M + 1], 629

H

Method: 10, RT: 1.62 min, MI: 496 [M + 1], 630

Method: 10, RT: 2.56 min, MI: 555 [M + 1],

Synthesis of2-{(R)-3-[2-(2-Phenylamino-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4ylamino]pyrrolidin-1-yl}-acetamide[631]

A sealed tube containing[2-(2-Phenylamino-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[573] (261 mg, 0.67 mmol) was charged with iodoacetamide (150 mg, 0.81mmol), cesium carbonate (0.88 g, 2.7 mmol) and acetonitrile (7.0 mL) washeated at 70° C. until complete. Partitioning between dichloromethaneand sat aq. NaHCO3, separation of the organic layer, drying (MgSO4),filtration, concentration and purification by RP-HPLC,acetonitrile/water gradient provided the title compound as a yellowishsolid (106 mg, 35% yield). HPLC: method: 10, RT: 1.61 min, MI: 446[M+1].

General Synthesis of Substituted4-amino-2-pyrazolyl-4-yl-thieno[3,2-d]pyrimidine Derivatives of GeneralFormula [F-156] (Scheme B25)

An 4,5-substituted-3-amino-thiophene-2-carboxylic acid amide derivativeof general formula [G-107] was subjected to a cyclisation reaction withan pyrazole aldehyde derivative of general formula [G-157] in thepresence of 4M hydrogen chloride in dioxane in a suitable solvent suchas methanol. The reaction is suitably conducted at an elevatedtemperature for example 140° C. in a microwave reactor for 20 minutes.Full aromatisation is subsequently achieved with2,3-dichloro-5,6-dicyanobenzoquinone in a suitable solvent such asdichloromethane at ambient temperature, to yield the 6,7-substituted2-pyrazolyl-4-yl-thieno [3,2-d]pyrimidin-4-ol, of general formula[G-155]. The corresponding 6,7-substituted 2-pyrazolyl-4-yl-thieno[3,2-d]pyrimidin-4-ol, of general formula [G-155] was reacted with2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solventsuch as DMA, DMF, NMP with a tertiary alkylamine base such as Et₃N,DIPEA or NMM and a catalytic amount of DMAP and used crude and reactedfurther with a primary or secondary amino derivative, of general formula[G-117]. After reaction work up, typically by a liquid-liquid extractionor purification by acidic ion exchange catch-release, the N-Bocderivatives were deprotected under acidic conditions with a strong acidsuch as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent suchas DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC.

Synthesis of 2-(5-Methyl-1H-pyrazol-4-yl)-thieno[3,2-d]pyrimidin-4-ol[BB-46]

A microwave vial was charged with 3-amino-thiophene-2-carboxylic acidamide (0.25 g, 1.76 mmol), 3-methyl-1H-pyrazole-4-carbaldehyde (165 mg,1.5 mmol), hydrogen chloride 4M in dioxane (7 l, 0.03 mmol) and methanol(2 ml). The reaction mixture was heated to 140° C. for 20 minutes undermicrowave irradiation. After completion, the mixture was concentratedunder reduced pressure. To a solution of the crude product indichloromethane (3 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone(440 mg, 1.93 mmol). The mixture was stirred at room temperature for 18hours. After completion, the precipitate formed was filtered and washedwith methanol. The residue was used without any further purification inthe next step. LCMS method: 8, RT: 2.48 min, MI: 233 [M+1]. 1H NMR(DMSO) 12.38 (1H, br s), 8.36 (1H, s), 8.16 (1H, d), 7.35 (1H, d), 2.56(3H, s).

Synthesis of[2-(5-Methyl-1H-pyrazol-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[633]

To a solution of2-(5-Methyl-1H-pyrazol-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-46] (0.28mg, 1.2 mmol) in DMA (10 ml) was added 2,4,6-triisopropylbenzenesulfonylchloride (438 mg, 1.45 mmol), triethylamine (0.34 ml, 2.4 mmol) and DMAP(16 mg, 0.12 mmol). The solution was stirred at room temperature for 4hours then (R)-(+)-1-Boc-3-aminopyrrolidine (220 mg, 1.2 mmol) was addedand the mixture was stirred at room temperature for 18 hours. Water wasadded and the mixture was extracted with DCM (50 ml), washed with brine(50 ml) and dried (MgSO₄), filtered and evaporated under reducedpressure. The crude reaction product was dissolved in DCM (5 ml) and TFA(2 ml) was added and the mixture stirred at room temperature for 2hours. After completion the mixture was loaded onto a SCX-2 cartridgeand washed with methanol. The product was released from the cartridgeusing a solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure followed by trituration in ether andthe crude product was purified by preparative HPLC (method B) to yieldthe title compound. LCMS method: 6, RT: 3.80 min, MI: 301 [M+1].

N*1*-[2-(5-Methyl-1H-pyrazol-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-3-(S)-phenyl-propane-1,2-diamine[634] was prepared according to the above procedure from2-(5-Methyl-1H-pyrazol-4-yl)-thieno[3,2-d]pyrimidin-4-ol [BB-46] and((S)-1-Aminomethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester togive the title compound: LCMS method: 6, RT: 3.65 min, MI: 365 [M+1].

VI. Biology

PKCι IC₅₀ Assay

Assays are based on the ability of PKCι to phosphorylate a commerciallyavailable peptide substrate in vitro. The peptide substrate is FAM-PKCεpseudopeptide derived peptide, and comprises the amino acid sequence5FAM-ERMRPRKRQGSVRRRV-NH₂. Recombinant, full-length human PKCι expressedin Sf21 insect cells is also commercially available. Recombinant,kinase-domain human PKCι is expressed and purified in-house.

The procedure below explains how dose response curves for inhibitors ofPKCι are obtained. The screen described is for a 384 well format but theassay can be adapted to 1536 or other formats as required.

Compounds to be tested are dissolved in 100% DMSO. Compounds are dilutedas required to give a final concentration of 4% DMSO (v/v) in the assay.1 μl is plated into 384 well black low-binding flat bottomed assayplates which are used immediately. Dilutions and additions of compoundto assay plates are carried out using Matrix WellMate® and MatrixPlateMate® Plus liquid handling systems.

On the day of the screen PKCι/substrate working solution, and ATPworking solution, are prepared in buffer containing 20 mM tris-HClpH7.5, 10 mM MgCl₂, 0.01% Triton X100, 250 μM EGTA and 1 mM DTT. Thefinal concentration of PKCι used varies depending on the batch ofprotein but is typically 15 pM. The final concentration of peptidesubstrate in the assay is 100 nM. ATP is used at a final concentrationof 150 μM or 2 μM in the assays containing full-length or kinase-domainPKCι respectively, which corresponds to five times or equal to the K_(M)^(APP) for ATP for each enzyme, respectively. The final bufferconcentration in the assay is 18 mM tris-HCl pH7.5, 9 mM MgCl₂, 0.009%Triton X100, 225 μM EGTA and 0.9 mM DTT. Relevant controls are included,namely no compound and no enzyme. 5 μl PKCι/substrate working solutionat 30 pM and 200 nM, respectively, is added to the wells, followed by 4μl ATP working solution at 375 μM or 62.5 μM for full-length orkinase-domain PKCι respectively, using a 16 channel Matrix pipette. Thereaction is allowed to incubate for 60 minutes at room temperature,before the reaction is stopped and developed by the addition of 20 μlIMAP™ development reagent (Molecular Devices). IMAP development reagentconsists of 0.25% (v/v) IMAP progressive binding reagent, 17% (v/v) IMAPprogressive binding buffer A and 3% (v/v) IMAP progressive bindingbuffer B. The plates are then incubated for 2 hours at room temperaturebefore being read using an appropriate plate reader, for example aMolecular Devices HT Analyst or a BMG Pherastar. Plates are read using afluorescence polarisation protocol with excitation at 485 nm andemission at 530 nm, and dichroic mirror at 505 nm.

Percentage inhibition values are calculated from fluorescencepolarisation values, using the no compound and no enzyme control valuesas 0% and 100% inhibition, respectively. IC50 determination is performedwith ExcelFit software (IDBS) using curve fit 205. Z′ factors aredetermined for each plate tested and are all above 0.5.

Results

Biological data for the Example compounds is presented in the followingtable. Activities are set forth as follows:

IC50 in IMAP assay against full length PKCi at 15 μM ATP:

-   -   A=<100 nM    -   B=100 nM to 1,000 nM    -   C=1,000 nM to 10,000 nM    -   D=10,000 nM to 40,000 nM

IC50 in IMAP assay against kinase domain PKCi at 2 μM ATP:

-   -   A*=<100 nM    -   B*=100 nM to 1,000 nM    -   C*=1,000 nM to 10,000 nM    -   D*=10,000 nM to 40,000 nM

Ex Activity Structure Name  1 C*

N,N-Dimethyl-N′-(2-pyridin- 4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-ethane- 1,2-diamine  2 B*

(R)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  3 B*

4-Piperazin-1-yl-2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine  4 B*

4-(4-Methyl-[1,4]diazepan-1- yl)-2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine  5 A*

(S)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  6 C*

(R)-4-Methylsulfanyl-N*1*- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-butane- 1,2-diamine  7 C*

(R)-3-(1H-Indol-3-yl)-N*1*- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  8 B*

4-((S)-3-Methyl-piperazin-1- yl)-2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine  9 C*

4-((3R,5S)-3,5-Dimethyl- piperazin-1-yl)-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine  10 C*

4-((2R,5S)-2,5-Dimethyl- piperazin-1-yl)-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine  11 D*

(1S,2S)-N-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)- cyclopropane-1,2-diamine  12 B

N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane- 1,2-diamine  13 B*

N-Methyl-N′-(2-pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2- diamine  14 B*

4-[1,4]Diazepan-1-yl-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine  15 B*

N*1*-Methyl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-ethane- 1,2-diamine  16 C*

(R)-4-Methyl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-pentane- 1,2-diamine  17 C*

(R)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-butane- 1,2-diamine  18 B*

4-(1S,4S)-2,5-Diaza- bicyclo[2.2.1]hept-2-yl-2- pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine  19 B*

(2-Pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-(R)- pyrrolidin-3-yl-amine  20 C*

(2-Pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-(S)- pyrrolidin-3-yl-amine  21 B*

N*1*-(7-Methyl-2-pyridin- 4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane- 1,2-diamine  22 C*

(S)-N*1*-(7-Methyl-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  23 C*

(R)-N*1*-(7-Methyl-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  24 B*

N*1*-(2-Pyridin-4-yl- 5,6,7,8,9,10-hexahydro-11- thia-1,3-diaza-cycloocta[a]inden-4-yl)- ethane-1,2-diamine  25 C*

(S)-N*1*-(2-Pyridin-4-yl- 5,6,7,8,9, 10-hexahydro-11-thia-1,3-diaza-cycloocta[a]inden-4- yl)-propane-1,2-diamine  26 C*

(R)-N*1*-(2-Pyridin-4-yl- 5,6,7,8,9, 10-hexahydro-11-thia-1,3-diaza-cycloocta[a]inden-4- yl)-propane-1,2-diamine  27 D

[4-(2-Amino-ethylamino)-2- pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-phenyl- methanone  28 B*

N*1*-(5-Isobutyl-2-pyridin- 4-yl-thieno[2,3- d]pyrimidin-4-yl)-ethane-1,2-diamine  29 B*

(S)-N*1*-(5-Isobutyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  30 C*

(R)-N*1*-(5-Isobutyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  31 C*

(S)-N*1*-(5-Ethyl-6-methyl- 2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  32 D*

(R)-N*1*-(5-Ethyl-6-methyl- 2-pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  33 C*

N*1*-(6-Ethyl-2-pyridin-4- yl-thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2-diamine  34 C*

(S)-N*1*-(6-Ethyl-2-pyridin- 4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane-1,2-diamine  35 C*

(R)-N*1*-(6-Ethyl-2-pyridin- 4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane-1,2-diamine  36 B*

N*1*-(5,6-Dimethyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2- diamine  37 C*

(S)-N*1*-(5,6-Dimethyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  38 C*

(R)-N*1*-(5,6-Dimethyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  39 B*

4-(2-Amino-ethylamino)-5- methyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidine-6- carboxylic acid amide  40 C*

N*1*-(6-Isopropyl-2-pyridin- 4-yl-thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2-diamine  41 D*

(R)-N*1*-(6-Isopropyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  42 C

N*1*-1,4-Dioxa-spiro[7.7]- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  43 C

N*1*-(7,7-Dimethyl-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-ethane-1,2- diamine  44 C

N*1*-(2-Pyridin-4-yl-5,8- dihydro-6H-thio- pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane- 1,2-diamine  45 D

N*1*-(2-Pyridin-4-yl-5,8- dihydro-6H- pyrano[4′3′:4,5]thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2- diamine  46 C

(S)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-3-p-tolyl- propane-1,2-diamine  47 B

(S)-3-(4-Methoxy-phenyl)- N*1*-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  48 B

(S)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-3-m-tolyl- propane-1,2-diamine  49 C

(S)-3-(2-Methoxy-phenyl)- N*1*-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  50 C

(S)-3-(4-Fluoro-phenyl)- N*1*-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  51 B

(S)-3-(2-Fluoro-phenyl)- N*1*-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  52 C

(R)-3-Naphthalen-1-yl-N*1*- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  53 B

(S)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-3-o-tolyl- propane-1,2-diamine  54 C

(S)-3-(3-Methoxy-phenyl)- N*1*-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  55 C

4-[(S)-2-Amino-3-(2-pyridin- 4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-ylamino)- propyl]-phenol  56 C

(S)-3-Pyridin-4-yl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  57 B

(S)-3-Pyridin-3-yl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  58 C

(S)-3-Pyridin-2-yl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  59 B

(S)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-3-thiazol- 4-yl-propane-1,2-diamine  60 C

(S)-4,4-Dimethyl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-pentane- 1,2-diamine  61 C

(R)-3-Benzo[b]thiophen-3-yl- N*1*-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  62 C

(R)-1-Piperidin-2-ylmethyl- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-amine  63 C

(S)-3-(1H-Indol-3-yl)-N*1*- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  64 D

(S)-3-(2-Methoxy-phenyl)- N*1*-(2-pyridin-4-yl-5,8- dihydro-6H-thio-pyrano[4′,3′:4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  65A

2-[(S)-2-Amino-3-(2-pyridin- 4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-ylamino)- propyl]-phenol  66 B

3-[(S)-2-Amino-3-(2-pyridin- 4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-ylamino)- propyl]-phenol  67 A*

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  68 C*

(S)-N*1*-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-butane-1,2- diamine  69 B*

(S)-N*1*-(7-Methyl-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-3-phenyl- propane-1,2-diamine 70 C

(R)-3-Phenyl-N*1*-(2- pyridin-4-yl-6,7,8,9- tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-yl)- propane-1,2-diamine  71 C*

(R)-3-Phenyl-N*1*-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  72 C

[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- 5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-phenyl- methanone  73 C

[4-((R)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- 5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-phenyl- methanone  74 B*

4-((S)-2-Amino-3-phenyl- propylamino)-5-methyl-2-pyridin-4-yl-thieno[2,3- d]pyrimidine-6-carboxylic acid amide  75 C*

(S)-N*1*-(6-Isopropyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-3-phenyl- propane-1,2-diamine  76 B*

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-5,6,7,8,9,10-hexahydro-11-thia-1,3-diaza- cycloocta[a]inden-4-yl)-propane-1,2-diamine  77 D

(S)-N*1*-(7,7-Dimethyl-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl)-3-phenyl- propane-1,2-diamine 78 C

(S)-3-Phenyl-N*1*-*-1,4- Dioxa-spiro[7.7]- (2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  79 B

(R)-3-Phenyl-N*1*-*-1,4- Dioxa-spiro[7.7]-(2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-propane- 1,2-diamine  80 B

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-5,8-dihydro-6H- thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl)- propane-1,2-diamine  81 C

(R)-3-Phenyl-N*1*-(2- pyridin-4-yl-5,8-dihydro-6H- thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl)- propane-1,2-diamine  82 C

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-5,8-dihydro-6H-pyrano[4′,3′:4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  83D

(R)-3-Phenyl-N*1*-(2- pyridin-4-yl-5,8-dihydro-6H-pyrano[4′,3′:4,5]thieno[2,3- d]pyrimidin-4-yl)-propane- 1,2-diamine  84B*

N*1*-(2-Pyridin-4-yl-6,7,8,9- tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-yl)- ethane-1,2-diamine  85 B*

4-Piperazin-1-yl-2-pyridin-4- yl-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza- benzo[a]azulene  86 B*

4-[1,4]Diazepan-1-yl-2- pyridin-4-yl- 6,7,8,9-tetrahydro-5H-10-thia-1,3- diaza-benzo[a]azulene  87 B*

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-6,7,8,9- tetrahydro-5H-10-thia-1,3-diaza-benzo[a]azulen-4-yl)- propane-1,2-diamine  88 B*

(S)-N*1*-(2-Pyridin-4-yl- 6,7,8,9-tetrahydro-5H-10- thia-1,3-diaza-benzo[a]azulen-4-yl)- propane-1,2-diamine  89 B*

(R)-N*1*-(2-Pyridin-4-yl- 6,7,8,9-tetrahydro-5H-10- thia-1,3-diaza-benzo[a]azulen-4-yl)- propane-1,2-diamine  90 C

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- 5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidine-7-carboxylic acid tert-butylester  91 C*

N*1*-(6-Methyl-5-phenyl-2- pyridin-4-yl-thieno[2,3-d]pyrimidin-4-yl)-ethane-1,2- diamine  92 C*

4-[1,4]Diazepan-1-yl-6- methyl-5-phenyl-2-pyridin-4-yl-thieno[2,3-d]pyrimidine  93 C*

5-(4-Bromo-phenyl)-4- [1,4]diazepan-1-yl-2-pyridin-4-yl-thieno[2,3-d]pyrimidine  94 A*

5-Methyl-4-piperazin-1-yl-2- pyridin-4-yl-thieno[2,3- d]pyrimidine  95B*

4-[1,4]Diazepan-1-yl-5- methyl-2-pyridin-4-yl- thieno[2,3-d]pyrimidine 96 D

4-((S)-2-Amino- propylamino)-2-pyridin-4-yl- 5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidine-7-carboxylic acid tert-butylester  97 C*

N*1*-[2-(3-Fluoro-pyridin-4- yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-ethane- 1,2-diamine  98 D*

N*1*-[2-(2-Fluoro-pyridin-4- yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-ethane- 1,2-diamine  99 C*

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-propane- 1,2-diamine 100 C*

(R)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-propane- 1,2-diamine 101 C

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-3-phenyl- propane-1,2-diamine102 D

(S)-N*1*-[2-(3-Methoxy- pyridin-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-3-phenyl- propane-1,2-diamine103 C

4-[4-((S)-2-Amino-3-phenyl- propylamino)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-2-yl]-pyridin- 3-ol 104 D

1-[4-(2-Amino-ethylamino)- 2-pyridin-4-yl-5,8-dihydro- 6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-2,2-dimethyl-propan-1-one 105 C

1-[4-(2-Amino-ethylamino)- 2-pyridin-4-yl-5,8-dihydro- 6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-ethanone 106 D

1-[4-(2-Amino-ethylamino)- 2-pyridin-4-yl-5,8-dihydro- 6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-propan-1- one 107 D

1-[4-(2-Amino-ethylamino)- 2-pyridin-4-yl-5,8-dihydro- 6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-2-methyl- propan-1-one108 D

[4-(2-Amino-ethylamino)-2- pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]- cyclopropyl-methanone109 D

[4-(2-Amino-ethylamino)-2- pyridin-4-yl-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-cyclobutyl- methanone 110D

1-[4-(2-Amino-ethylamino)- 2-pyridin-4-yl-5,8-dihydro- 6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-pentan-1- one 111 D

1-[4-(2-Amino-ethylamino)- 2-pyridin-4-yl-5,8-dihydro- 6H-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-7-yl]-2- dimethylamino-ethanone112 D

N*1*-(7-Ethyl-2-pyridin-4- yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-4-yl)-ethane- 1,2-Diamine 113 D

N*1*-(7-Methyl-2-pyridin-4- yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-4-yl)-ethane- 1,2-diamine 114 D

N*1*-(7-Isobutyl-2-pyridin- 4-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3- d]pyrimidin-4-yl)-ethane- 1,2-diamine 115D*

4-[4-(4-Methyl-benzyl)- piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 116 D*

4-(4-Benzyl-piperazin-1-yl)- 2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 117 D*

4-[4-(4-Bromo-benzyl)- piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 118 C*

2-Pyridin-4-yl-4-(4-pyridin- 4-ylmethyl-piperazin-1-yl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 119 C*

4-(4-Ethyl-piperazin-1-yl)-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 120 D*

2-Pyridin-4-yl-4-(4-pyridin- 2-ylmethyl-piperazin-1-yl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 121 D*

2-Pyridin-4-yl-4-[4-(4- trifluoromethyl-benzyl)-piperazin-1-yl]-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine122 D*

4-[4-(4-Chloro-benzyl)- piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 123 D*

4-[4-(2-Chloro-benzyl)- piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 124 D*

4-[4-(3-Chloro-benzyl)- piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 125 C*

4-(4-Methyl-piperazin-1-yl)- 2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 126 D*

3-[4-(2-Pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-piperazin- 1-ylmethyl]-phenol 127 D*

4-[4-(3-Bromo-benzyl)- piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 128 D*

4-[4-(6-Bromo-pyridin-3- ylmethyl)-piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 129D*

4-(4-Butyl-piperazin-1-yl)- 2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 130 D*

2-Pyridin-4-yl-4-(4-pyridin- 3-ylmethyl-piperazin-1-yl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 131 D*

4-[4-(3-Bromo-pyridin-4- ylmethyl)-piperazin-1-yl]-2-pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 132D*

4-(4-Phenethyl-piperazin-1- yl)-2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 133 D*

4-(4-Propyl-piperazin-1-yl)- 2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 134 D*

4-(4-Isobutyl-piperazin-1- yl)-2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 135 C*

Dimethyl-[2-(2-pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-ethyl]- amine 136 B*

2-(2-Pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)- ethylamine 137 C*

Methyl-[2-(2-pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-ethyl]- amine 138 C*

(S)-3-Methyl-1-(2-pyridin- 4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- butylamine 139 C

2-Pyridin-4-yl-4-((R)- pyrrolidin-3-yloxy)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 140 C*

2-Pyridin-4-yl-4-((S)- pyrrolidin-3-yloxy)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 141 C*

4-(Piperidin-3-yloxy)-2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 142 D*

(R)-2-Phenyl-1-(2-pyridin- 4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- ethylamine 143 B*

(S)-2-Phenyl-1-(2-pyridin- 4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- ethylamine 144 B*

(S)-1-Methyl-2-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 145 C*

(R)-1-Methyl-2-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 146 C*

(R)-3-Methyl-1-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- butylamine 147 D*

(R)-1-Phenyl-2-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 148 D*

(R)-2-Methyl-1-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- propylamine 149 C*

(R)-1-(2-Pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxymethyl)- propylamine 150 C*

(S)-1-(2-Pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxymethyl)- propylamine 151 C*

(S)-2-Methyl-1-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- propylamine 152 C*

4-(Azetidin-3-yloxy)-2- pyridin-4-yl- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 153 C*

2-Pyridin-4-yl-4-((R)-1- pyrrolidin-2-ylmethoxy)- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 154 C*

2-Pyridin-4-yl-4-((S)-1- pyrrolidin-2-ylmethoxy)- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 155 C*

(S)-1-Phenyl-2-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 156 C*

(S)-1-Cyclohexyl-2-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 157 C*

(S)-2-Cyclohexyl-1-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- ethylamine 158 D*

(S)-2-(1H-Indol-3-yl)-1-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- ethylamine 159 C*

(S)-1-(4-Methoxy-benzyl)-2- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 160 D*

(S)-1-Naphthalen-2-ylmethyl- 2-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 161 C*

(S)-1-Naphthalen-1-ylmethyl- 2-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 162 D*

(S)-1-(4-Fluoro-benzyl)-2-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 163 C*

(S)-1-(3-Fluoro-benzyl)-2-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 164 C*

(S)-1-(2-Fluoro-benzyl)-2- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 165 C*

(S)-1-(3-Methyl-benzyl)-2- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 166 C*

(S)-1-(4-Methyl-benzyl)-2- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 167 D*

(R)-3-Phenyl-1-(2-pyridin-4- yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxymethyl)- propylamine 168 C*

(S)-2-(2-Pyridin-4-yl- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-1- thiophen-2-ylmethyl- ethylamine 169 D*

(R)-1-(4-Methoxy-benzyl)-2- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 170 D*

(R)-2-(2-Pyridin-4-yl-5,6,7,8- tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-1- thiophen-2-ylmethyl- ethylamine 171 C*

(S)-1-(4-Bromo-benzyl)-2-(2- pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 172 D*

(R)-1-Naphthalen-2- ylmethyl-2-(2-pyridin-4-yl- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 173 C*

(R)-1-Naphthalen-1- ylmethyl-2-(2-pyridin-4-yl- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 174 C*

(S)-1-(2-Methyl-benzyl)-2- (2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 175 D*

(S)-1-(1H-Imidazol-4- ylmethyl)-2-(2-pyridin-4-yl- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 176 D*

(R)-1-Benzo[b]thiophen-3- ylmethyl-2-(2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)-ethylamine 177 D*

(S)-1-Benzo[b]thiophen-3- ylmethyl-2-(2-pyridin-4-yl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)-ethylamine 178 C*

4-((R)-1-Piperidin-2- ylmethoxy)-2-pyridin-4-yl- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 179 D*

4-((S)-1-Piperidin-2- ylmethoxy)-2-pyridin-4-yl- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 180 C*

(S)-1-(3-Methoxy-benzyl)- 2-(2-pyridin-4-yl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yloxy)- ethylamine 181 B*

N*1*-[2-(1H-Pyrazol-4-yl)- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-ethane- 1,2-diamine 182 B*

N*1*-[2-(3,5-Dimethyl-1H- pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-ethane- 1,2-diamine 183 B*

(S)-3-Phenyl-N*1*-[2-(1H- pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-propane- 1,2-diamine 184 C*

(S)-N*1*-[2-(3,5-Dimethyl- 1H-pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-3-phenyl- propane-1,2-diamine185 B*

4-Piperazin-1-yl-2-(1H- pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 186 B*

4-[1,4]Diazepan-1-yl-2-(1H- pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 187 B*

(S)-N*1*-[2-(1H-Pyrazol-4- yl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-propane- 1,2-diamine 188 C*

(R)-N*1*-[2-(1H-Pyrazol-4- yl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-propane- 1,2-diamine 189 B*

[2-(1H-Pyrazol-4-yl)- 5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-(R)- pyrrolidin-3-yl-amine 190 B*

2-(3,5-Dimethyl-1H-pyrazol- 4-yl)-4-piperazin-1-yl- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine 191 B*

4-[1,4]Diazepan-1-yl-2-(3,5- dimethyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 192 C*

(S)-N*1*-[2-(3,5-Dimethyl- 1H-pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-propane- 1,2-diamine 193 D*

(R)-N*1*-[2-(3,5-Dimethyl- 1H-pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-propane- 1,2-diamine 194 B*

[2-(3,5-Dimethyl-1H-pyrazol- 4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-(R)- pyrrolidin-3-yl-amine195 >60 μM

N*1*-[2-(1-Methyl-1H- pyrazol-4-yl)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-yl]-ethane- 1,2-diamine 196 C

4-((S)-3-Benzyl-piperazin-1- yl)-2-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3- d]pyrimidine 300 A

(S)-N*1*-(7-Bromo-6- methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 301 C*

6-Phenyl-4-piperazin-1-yl- 2-pyridin-4-yl-thieno[3,2- d]pyrimidine 302A*

(S)-N*1*-(7-Methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 303 D

(S)-N*1*-(7-Bromo-6- tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl)-3-(2-methoxy-phenyl)- propane-1,2-diamine304 A

(S)-N*1*-[7-Bromo-2-(4- methyl-thiazol-5-yl)- thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 305 B

(S)-N*1*-(7-Bromo-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 306 A

(S)-N*1*-(7-Chloro-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 307 D*

(S)-N*1*-(6-tert-Butyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 308 D*

(R)-N*1*-(6-tert-Butyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 309 C

N*1*-(6,7-Dimethyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-ethane-1,2-diamine 310 C

N*1*-[7-(4-Bromo- phenyl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-ethane-1,2-diamine 311 D*

N*1*-(6-tert-Butyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-ethane-1,2-diamine 312 C*

(7-Methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl- amine 313 D*

N*1*-(6-Phenyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-ethane-1,2-diamine 314 B

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 315 D

((3S,4S)-1-Benzyl-4- fluoro-pyrrolidin-3-yl)-(2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-amine 316 C

(R)-Piperidin-3-yl-(2- pyridin-4-yl- thieno[3,2-d]pyrimidin-4- yl)-amine317 C

(2-Pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-(R)- pyrrolidin-3-yl-amine318 D

(R)-1-(2-Pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-pyrrolidin-3-ylamine 319 C

(3S,4S)-4-(2-Pyridin-4-yl- thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidin-3-ol 320 D

2-[(R)-3-(2-Pyridin-4-yl- thieno[3,2-d]pyrimidin-4- ylamino)-pyrrolidin-1-yl]-acetamide 321 D

((3S,4R)-4-Fluoro- pyrrolidin-3-yl)- (2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-amine 322 C

[2-(3-Chloro-pyridin-4- yl)-thieno[3,2- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 323 C

(S)-N*1*-[2-(3-Chloro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 324 D

(S)-N*1*-(6-tert-Butyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 325 B

(S)-N*1*-(6,7-Dimethyl- 2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 326 C

(S)-N*1*-[7-(4-Bromo- phenyl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 327 C

(R)-N*1*-[7-(4-Bromo- phenyl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 328 B

(7-Bromo-6-methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine 329 C

(R)-N*1*-(7-Bromo-6- methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 330 C

(R)-N*1*-(7-Bromo-6- methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine 331 C

(S)-N*1*-(7-Bromo-6- methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine 332 C

(7-Bromo-6-methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-(S)-pyrrolidin-3-yl-amine 333 D

N*1*-(7-Bromo-6-tert- butyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-ethane-1,2-diamine 334 C

(S)-N*1*-(7-Bromo-6- tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl)-3-phenyl-propane-1,2- diamine 335 D

(R)-N*1*-(7-Bromo-6- tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl)-3-phenyl-propane-1,2- diamine 336 A

(S)-N*1*-(7-Bromo-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 337 B

(S)-N*1*-(6-Bromo-7- methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 338 D

2-(7-Bromo-2-pyridin-4- yl-thieno[3,2-d]pyrimidin- 4-ylamino)-acetamide339 D

N′-(7-Bromo-2-pyridin-4- yl-thieno[3,2-d]pyrimidin- 4-yl)-N,N-dimethyl-ethane-1,2-diamine 340 B

(6-Bromo-7-methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine 341 D

(7-Bromo-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4- yl)-(S)-1-pyrrolidin-2-ylmethyl-amine 342 D

(7-Bromo-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4- yl)-(R)-1-pyrrolidin-2-ylmethyl-amine 343 B

(7-Bromo-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-(R)-piperidin-3-yl- amine 344 C

(7-Bromo-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-(S)-pyrrolidin-3-yl- amine 345 C

N-(7-Bromo-2-pyridin-4- yl-thieno[3,2-d]pyrimidin-4-yl)-N′-methyl-ethane- 1,2-diamine 346 C

(S)-N*1*-(7-Bromo-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-4-methyl-pentane-1,2- diamine 347 B

(S)-N*1*-(7-Bromo-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-methyl-butane-1,2- diamine 348 B

(S)-N*1*-(7-Bromo-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-cyclohexyl-propane-1,2- diamine 349 B

N*1*-(7-Bromo-2-pyridin- 4-yl-thieno[3,2- d]pyrimidin-4-yl)-ethane-1,2-diamine 350 B

7-Bromo-4-piperazin-1-yl- 2-pyridin-4-yl-thieno[3,2- d]pyrimidine 351 A

(7-Bromo-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl- amine 352 C

[7-Bromo-2-(3-fluoro- pyridin-4-yl)- thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl- amine 353 D

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-propane-1,2-diamine 354 D

[2-(3-Fluoro- pyridin-4-yl)- thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl- amine 355 C

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 356 D*

6-(4-tert-Butyl-phenyl)-4- [1,4]diazepan-1-yl-2-pyridin-4-yl-thieno[3,2- d]pyrimidine 357 D

6-(4-tert-Butyl-phenyl)-4- piperazin-1-yl-2-pyridin- 4-yl-thieno[3,2-d]pyrimidine 358 D*

(R)-N*1*-[6-(4-tert-Butyl- phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-propane-1,2-diamine 359 D*

(S)-N*1*-[6-(4-tert-Butyl- phenyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-propane-1,2-diamine 360 D*

N*1*-[6-(4-tert-Butyl- phenyl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-ethane-1,2-diamine 361 B*

(S)-N*1*-(7-Methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 362 B*

4-[1,4]Diazepan-1-yl-7- methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidine363 B*

7-Methyl-4-piperazin-1- yl-2-pyridin-4-yl- thieno[3,2-d]pyrimidine 364C*

(7-Methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-(S)-pyrrolidin-3-yl- amine 365 C*

N*1*-Methyl-N*1*-(7- methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-ethane-1,2-diamine 366 D*

(R)-N*1*-(6-Phenyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 367 D*

(S)-N*1*-(6-Phenyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 368 C*

4-[1,4]Diazepan-1-yl-6- phenyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidine369 C*

(R)-N*1*-(7-Methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-propane-1,2-diamine 370 B*

N*1*-(7-Methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-ethane-1,2-diamine 371 B*

9-Chloro-4-[1,4]diazepan- 1-yl-2-pyridin-4-yl- benzo[4,5]thieno[3,2-d]pyrimidine 372 B*

(S)-N*1*-(9-Chloro-2- pyridin-4-yl- benzo[4,5]thieno[3,2-d]pyrimidin-4-yl)-3- phenyl-propane-1,2- diamine 373 B*

(S)-N*1*-(9-Chloro-2- pyridin-4-yl- benzo[4,5]thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 374 B*

(R)-N*1*-(9-Chloro-2- pyridin-4-yl- benzo[4,5]thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 375 C*

N*1*-(2-Pyridin-4-yl- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)-ethane- 1,2-diamine 376 D*

4-Piperazin-1-yl-2- pyridin-4-yl- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 377 C*

4-[1,4]Diazepan-1-yl-2- pyridin-4-yl- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 378 C*

(S)-N*1*-(2-Pyridin-4-yl- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 379 D*

(R)-N*1*-(2-Pyridin-4-yl- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 380 C*

7,9-Dimethyl-4-piperazin- 1-yl-2-pyridin-4-yl-pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidine 381 C*

4-[1,4]Diazepan-1-yl-7,9- dimethyl-2-pyridin-4-yl-pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidine 382 B*

(S)-N*1*-(7,9-Dimethyl- 2-pyridin-4-yl- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 383 C*

(R)-N*1*-(7,9-Dimethyl- 2-pyridin-4-yl- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 384 C*

(9-Chloro-2-pyridin-4-yl- benzo[4,5]thieno[3,2- d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine 385 C*

N*1*-(9-Chloro-2- pyridin-4-yl- benzo[4,5]thieno[3,2-d]pyrimidin-4-yl)-N*1*- methyl-ethane-1,2- diamine 386 B*

N*1*-(9-Chloro-2- pyridin-4-yl- benzo[4,5]thieno[3,2-d]pyrimidin-4-yl)-ethane- 1,2-diamine 387 B*

9-Chloro-4-piperazin-1-yl- 2-pyridin-4-yl- benzo[4,5]thieno[3,2-d]pyrimidine 388 A

(S)-N*1*-[6-Methyl-7- (2H-pyrazol-3- yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 389 C

[7-Methyl-6-(2H-pyrazol- 3-yl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl- amine 390 A

(S)-3-Phenyl-N*1*-[7- (2H-pyrazol-3-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]- propane-1,2-diamine 391 C

(S)-N*1*-[7-(2-Methyl- 2H-pyrazol-3-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 392 C

N*1*-[7-(3,5-Dimethyl- isoxazol-4-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 393 B

(S)-3-Phenyl-N*1*-[7- (1H-pyrazol-4- yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-propane-1,2-diamine 394 C

(S)-N*1*-[7-(1-Isobutyl- 1H-pyrazol-4-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 395 C

(S)-N*1*-[7-(4-Methyl- thiophen-2-yl)-2-pyridin- 4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 396 B

(S)-N*1*-[7-(3-Methyl- thiophen-2-yl)-2-pyridin- 4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 397 B

(S)-3-Phenyl-N*1*-[2- pyridin-4-yl-7-(1H-pyrrol- 2-yl)-thieno[3,2-d]pyrimidin-4-yl]- propane-1,2-diamine 398 B

(S)-3-Phenyl-N*1*-[2- pyridin-4-yl-7-(1H-pyrrol- 3-yl)-thieno[3,2-d]pyrimidin-4-yl]- propane-1,2-diamine 399 C

(S)-N*1*-{7-[(tert-Butyl- dimethyl-silanyl)- ethynyl]-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl}-3-phenyl-propane-1,2- diamine 400 A

(S)-N*1*-[7-(3-Methoxy- prop-1-ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 401 B

(S)-N*1*-(7-Pent-1-ynyl- 2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 402 B

(S)-3-Phenyl-N*1*-(7- phenylethynyl-2-pyridin- 4-yl-thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 403 A

[7-(2H-Pyrazol-3-yl)-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 404 B

(S)-N*1*-[7-((E)-3- Methoxy-propenyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 405 A

(S)-N*1*-[7-((E)-2- Cyclopropyl-vinyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 406 C

(S)-N*1*-[7-((E)-3,3- Dimethyl-but-1-enyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 407 A

(S)-3-Phenyl-N*1*-[7- ((Z)-propenyl)-2-pyridin- 4-yl-thieno[3,2-d]pyrimidin-4-yl]- propane-1,2-diamine 408 A

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-7-vinyl- thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine 409 B

(S)-N*1*-[7-(4-Fluoro- phenyl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 410 C

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-7-pyridin-3-yl-thieno[3,2-d]pyrimidin- 4-yl)-propane-1,2-diamine 411 C

(S)-N*1*-[7-(1-Methyl- 1H-pyrazol-4-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 412 C

(S)-N*1*-[7-(5-Methyl- furan-2-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 413 A

(S)-N*1*-(7-Cyclopropyl- 2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 414 B

(R)-3-Phenyl-N*1*-[7- (1H-pyrazol-3-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]- propane-1,2-diamine 415 C

(S)-N*1*-[7-(1-Methyl- 1H-pyrazol-3-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 416 A

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-(1H- pyrazol-3-yl)-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 417 B

(S)-3-Phenyl-N*1*-(7- phenyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine 418 B

(S)-N*1*-[7-(5- Cyclopropyl-1H-pyrazol- 3-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 419 B

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-(1H- pyrrol-2-yl)-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 420 B

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-(1H- pyrrol-3-yl)-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 421 C

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-(5- trifluoromethyl-2H-pyrazol-3-yl)-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 422 C

(R)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-pyrimidin- 5-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 423 C

(R)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-pyridin-3-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 424 C

{4-[4-((R)-2-Amino-3- phenyl-propylamino)-2-(3- fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7- yl]-phenyl}-methanol 425 C

{3-[4-((R)-2-Amino-3- phenyl-propylamino)-2-(3- fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7- yl]-phenyl}-methanol 426 B

(R)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-furan-3-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 427 C

(R)-N*1*-[7-(4- Aminomethyl-phenyl)-2- (3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 428 C

(R)-N*1*-[7-(3,5- Dimethyl-isoxazol-4-yl)- 2-(3-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 429 C

(R)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 430 C

(R)-N*1*-[7-(4-Fluoro- phenyl)-2-(3-fluoro- pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 431 C

(R)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-thiophen- 3-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 432 B

(R)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-furan-2-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 433 C

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-o-tolyl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 434 C

(S)-N*1*-[2-(3-Fluoro- pyridin-4-yl)-7-phenyl- thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 435 C

S)-N*1*-[7-(4- Aminomethyl-furan-2- yl)-2-(3-fluoro-pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 436 D

(S)-N*1*-[6-tert-Butyl-7- (3-fluoro-phenyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 437 C

(S)-N*1*-[6-tert-Butyl-7- (1H-pyrazol-4-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 438 C

(S)-N*1*-[7-(6-Fluoro- pyridin-3-yl)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 439 D

(S)-N*1*-[7-(4-Methoxy- pyridin-3-yl)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 440 D

(S)-N*1*-[7-(2- Isopropoxy-6-methoxy- phenyl)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 441 D

(S)-N*1*-[6-tert-Butyl-7- (3-methoxy-phenyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 442 D

(S)-N*1*-[6-tert-Butyl-7- (4-fluoro-phenyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 443 D

(S)-N*1*-[6-tert-Butyl-7- (6-fluoro-pyridin-3-yl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 444 D

(S)-N*1*-[7-(3-Amino- phenyl)-6-tert-butyl-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 445 D

(S)-N*1*-(6-tert-Butyl-7- furan-3-yl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl)-3-phenyl-propane-1,2- diamine 446 D

(S)-N*1*-[7-(5-Fluoro-2- isopropoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 447 C

(S)-N*1*-[6-tert-Butyl-7- (5-methyl-thiophen-2-yl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 448 C

(S)-N*1*-[6-tert-Butyl-7- (4-methylamino-phenyl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 449 C

(S)-N*1*-(6-Methyl-7- phenyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 450 D

(S)-N*1*-[7-(2-Methoxy- 5-methyl-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 451 D

(S)-N*1*-(6-tert-Butyl-7- phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl)-3-phenyl-propane-1,2- diamine 452 D

(S)-N*1*-[7-(2-Chloro-6- trifluoromethyl-phenyl)-6-methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 453 D

(S)-N*1*-[7-(2-Chloro-6- methoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 454 D

(S)-N*1*-[7-(2,6- Dimethoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 455 D

(S)-N*1*-[7-(2-Isobutoxy- 6-methoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 456 D

(S)-N*1*-[7-(3-Methoxy- pyridin-4-yl)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 457 D

(S)-N*1*-[7-(2,4- Dimethyl-thiazol-5-yl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 458 D

(S)-N*1*-[7-(2- Isopropoxy-5-methyl- phenyl)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 459 D

(S)-N*1*-[6-Methyl-7-(2- methyl-pyridin-3-yl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 460 D

(S)-N*1*-[7-(5-Chloro-2- isopropoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 461 D

(S)-N*1*-[7-(5-tert-Butyl- 2-methoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 462 D

(S)-N*1*-[7-(5-Isopropyl- 2-methoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 463 D

(S)-N*1*-[7-(5-Chloro-2- ethoxy-phenyl)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 464 D

(S)-N*1*-[7-(2-Methoxy- 5-trifluoromethyl-phenyl)-6-methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 465 D

(S)-N*1*-[7-(2-Methoxy- pyridin-3-yl)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine 466 D

(S)-N*1*-[7-(2,5- Dimethoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 467 D

(S)-N*1*-[7-(5-Fluoro-2- methoxy-phenyl)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 468 C

(S)-N*1*-[6-tert-Butyl-7- (2H-pyrazol-3-yl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 469 D

[7-Methyl-6-(2-methyl- 2H-pyrazol-3- yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-l]-(R)-pyrrolidin-3-yl- amine 470 D

Cyclopentanecarboxylic acid [4-((S)-2-amino-3- phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-7-yl]-amide 471 D

2,2-Dimethyl-N-[2- pyridin-4-yl-4-((R)- pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-7- yl]-butyramide 472 D

N-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-2,2- dimethyl-butyramide 473 D

Cyclohexanecarboxylic acid [2-pyridin-4-yl-4- ((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-7-yl]-amide 474 D

Cyclohexanecarboxylic acid [4-((S)- 2-amino-3-phenyl-propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidin- 7-yl]-amide 475 D

Cyclopentanecarboxylic acid [2-pyridin-4-yl-4- ((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-7-yl]-amide 476 D*

7-Methyl-2-pyridin-4-yl- 4-((R)-1-pyrrolidin-2- ylmethoxy)-thieno[3,2-d]pyrimidine 477 D*

(R)-1-(9-Chloro-2-pyridin- 4-yl-benzo[4,5]thieno[3,2- d]pyrimidin-4-yloxymethyl)-2-phenyl- ethylamine 478 D*

9-Chloro-2-pyridin-4-yl-4- ((R)-1-pyrrolidin-2- ylmethoxy)-benzo[4,5]thieno[3,2- d]pyrimidine 479 C*

9-Chloro-2-pyridin-4-yl-4- ((S)-1-pyrrolidin-2- ylmethoxy)-benzo[4,5]thieno[3,2- d]pyrimidine 480 D*

7-Methyl-2-pyridin-4-yl- 4-((S)-1-pyrrolidin-2- ylmethoxy)-thieno[3,2-d]pyrimidine 481 D*

(S)-1-(7-Methyl-2-pyridin- 4-yl-thieno[3,2- d]pyrimidin-4-yloxymethyl)-2-phenyl- ethylamine 482 D*

(R)-1-(7-Methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yloxymethyl)-2-phenyl- ethylamine 483 D*

7-Methyl-2-pyridin-4-yl- 4-((S)-pyrrolidin-3-yloxy)-thieno[3,2-d]pyrimidine 484 C*

7-Methyl-2-pyridin-4-yl- 4-((R)-pyrrolidin-3- yloxy)-thieno[3,2-d]pyrimidine 485 B

N*4*-((S)-2-Amino-3- phenyl-propyl)-N*7*- phenyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidine- 4,7-diamine 486 A

N*4*-((S)-2-Amino-3- phenyl-propyl)-2-pyridin- 4-yl-N*7*-pyridin-2-yl-thieno[3,2-d]pyrimidine- 4,7-diamine 487 C

2-Pyridin-4-yl-N*7*- pyridin-2-yl-N*4*-(R)- pyrrolidin-3-yl-thieno[3,2-d]pyrimidine-4,7-diamine 488 B

N*4*-((S)-2-Amino-3- phenyl-propyl)-2-pyridin- 4-yl-N*7*-pyrimidin-2-yl-thieno[3,2-d]pyrimidine- 4,7-diamine 489 C

N*4*-((S)-2-Amino-3- phenyl-propyl)-2-pyridin- 4-yl-N*7*-pyrimidin-4-yl-thieno[3,2-d]pyrimidine- 4,7-diamine 490 A

N*4*-((S)-2-Amino-3- phenyl-propyl)-N*7*-(5- methyl-isoxazol-3-yl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidine-4,7-diamine 491 C

N*4*-((S)-2-Amino-3- phenyl-propyl)- 2-(3-fluoro-pyridin-4-yl)-N*7*-phenyl-thieno[3,2- d]pyrimidine-4,7-diamine 492 D

2-(3-Fluoro-pyridin-4-yl)- N*4*-(R)- pyrrolidin-3-yl-N*7*-m-tolyl-thieno[3,2- d]pyrimidine-4,7-diamine 493 D

N*7*-(4-Fluoro-phenyl)- 2-(3-fluoro- pyridin-4-yl)-N*4*-(R)-pyrrolidin-3-yl-thieno[3,2- d]pyrimidine-4,7-diamine 494 D

2-(3-Fluoro-pyridin-4-yl)- N*7*-pyridin-3-yl-N*4*- (R)-pyrrolidin-3-yl-thieno[3,2-d]pyrimidine- 4,7-diamine 495 D

2-(3-Fluoro-pyridin-4-yl)- N*7*-pyridin-2-yl-N*4*- (R)-pyrrolidin-3-yl-thieno[3,2-d]pyrimidine- 4,7-diamine 496 D

2-(3-Fluoro-pyridin-4-yl)- N*7*-(5-methyl-isoxazol-3-yl)-N*4*-(R)-pyrrolidin- 3-yl-thieno[3,2- d]pyrimidine- 4,7-diamine497 D

2-(3-Fluoro-pyridin-4-yl)- N*7*-isoxazol-3-yl-N*4*- (R)-pyrrolidin-3-yl-thieno[3,2-d]pyrimidine- 4,7-diamine 498 C

2-(3-Fluoro-pyridin-4-yl)- N*4*-(R)-pyrrolidin-3-yl-N*7*-o-tolyl-thieno[3,2- d]pyrimidine-4,7-diamine 499 C

N*7*-(3-Fluoro-phenyl)- 2-(3-fluoro- pyridin-4-yl)-N*4*-(R)-pyrrolidin-3-yl-thieno[3,2- d]pyrimidine-4,7-diamine 500 B

N*7*-(2-Fluoro-phenyl)- 2-(3-fluoro- pyridin-4-yl)-N*4*-(R)-pyrrolidin-3-yl-thieno[3,2- d]pyrimidine-4,7-diamine 501 B

4-[4-((S)-2-Amino-3- phenyl-propylamino)-2-(3- fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7- yl]-but-3-yn-1-ol 502 C

2-Methyl-4-[7-methyl-2- pyridin-4-yl-4-((R)- pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-6- yl]-but-3-yn-2-ol 503 B

2-Methyl-4-[6-methyl-2- pyridin-4-yl-4-((R)- pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-7- yl]-but-3-yn-2-ol 504 A

4-[4-((S)-2-Amino-3- phenyl-propylamino)-6- methyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7- yl]-2-methyl-but-3-yn-2-ol 505 C

4-[4-((S)-2-Amino-3- phenyl-propylamino)-6- tert-butyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7- yl]-2-methyl-but-3-yn-2-ol 506 A

3-[4-((S)-2-Amino-3- phenyl-propylamino)-2-(3- fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7- yl]-prop-2-yn-1-ol 507 B

1-[4-((S)-2-Amino-3- phenyl-propylamino)-2-(3- fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7- ylethynyl]-cyclobutanol 508 B

(S)-4-[4-((S)-2-Amino-3- phenyl-propylamino)-2-(3- fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7- yl]-but-3-yn-2-ol 509 B

4-[4-((S)-2-Amino-3- phenyl-propylamino)-2-(3- fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-7- yl]-2-methyl-but-3-yn-2-ol 510 A

4-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-2- methyl-but-3-yn-2-ol 511 C

(S)-N*1*-[7-(3,3- Dimethyl-but-1-ynyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 512 A

(S)-N*1*-(7- Cyclopropylethynyl-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-3- phenyl-propane-1,2- diamine 513 A

4-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-but-3- yn-2-ol 514 B

2-Methyl-4-[2-pyridin-4- yl-4-((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-7-yl]-but-3- yn-2-ol 515 A

3-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-prop-2- yn-1-ol 516 C

(S)-N*1*-[7-(3-Amino-3- methyl-but-1-ynyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 517 A

(S)-4-[2-Pyridin-4-yl-4- ((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-7-yl]-but-3- yn-2-ol 518 B

(S)-N*1*-[7-(3-Methyl- but-1-ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 519 C

4-[2-(3-Fluoro-pyridin-4- yl)-4-((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-7-yl]-2- methyl-but-3-yn-2-ol 520 B

(S)-N*1*-[7-(3-Methoxy- 3-methyl-but-1-ynyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 521 A

S)-1-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-pent-1- yn-3-ol 522 C

(S)-1-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-4- methyl-hept-1-yn-3-ol 523 B

(S)-1-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-3- methyl-pent-1-yn-3-ol 524 C

(S)-1-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-3,4- dimethyl-pent-1-yn-3-ol 525 C

1-[4-(2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 7-yl]-3-ethyl-pent-1-yn-3- ol 526 B

(S)-1-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-hex-1- yn-3-ol 527 D

(S)-4-[2-(3-Fluoro- pyridin-4-yl)-4- ((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-7-yl]-but-3- yn-2-ol 528 A

2-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-ylethynyl]- cyclopentanol 529 B

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-7-pyridin-2- ylethynyl-thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 530 B

(S)-N*1*-[7-(2-Fluoro- phenylethynyl)-2-pyridin- 4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 531 A

4-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-but-3- yn-1-ol 532 A

1-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-ylethynyl]- cyclopropanol 533 A

(S)-4-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-but-3- yn-2-ol 534 A

(R)-4-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-but-3- yn-2-ol 535 C

5-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-pent-4- yn-1-ol 536 A

5-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-pent-4- yn-2-ol 537 B

5-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-2- methyl-pent-4-yn-2-ol 538 B

(S)-N*1*-[7-(3- Methylamino-prop-1- ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 539 A

1-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-ylethynyl]- cyclobutanol 540 B

(S)-5-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-pent-4- yn-2-ol 541 A

(S)-N*1*-(7-Ethynyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 542 A

(S)-3-Phenyl-N*1*-(7- prop-1-ynyl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl)-propane-1,2-diamine 543 C

(6-Ethynyl-7-methyl-2- pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl- amine 544 A

(S)-N*1*-[7-((R)-3- Fluoro-but-1-ynyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 545 A

(S)-N*1*-[7-(3-Fluoro- prop-1-ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 546 B

(S)-N*1*-[7-(4-Fluoro- but-1-ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidine 547 A

(S)-3-Phenyl-N*1*-[2- pyridin-4-yl-7-(2H- [1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidin-4- yl]-propane-1,2-diamine 548 B

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-7-thiazol-4- ylethynyl-thieno[3,2-d]pyrimidin-4-yl)- propane-1,2-diamine 549 A

(S)-3-Phenyl-N*1*-[7- (1H-pyrazol-3-ylethynyl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]- propane-1,2-diamine 550 C

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid dimethylamide 551 B

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid propylamide 552 C

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid diethylamide 553 A

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid methylamide 554 B

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid ethylamide 555 C

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid isopropylamide 556 B

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid cyclopropylamide 557 C

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7-carboxylic acid tert-butylamide 558 B

(E)-3-[4-((S)-2-Amino-3- phenyl-propylamino)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-acrylic acid 559 B

(7-Ethynyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl- amine 560 A

4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4- yl-thieno[3,2-d]pyrimidine-7- carbonitrile 561 B

(S)-3-Phenyl-N*1*-(7- pyrazol-1-yl-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl)-propane-1,2-diamine 562 B

(S)-3-Phenyl-N*1*-(2- pyridin-4-yl-7- [1,2,3]triazol-1-yl-thieno[3,2-d]pyrimidin-4- yl)-propane-1,2-diamine 563 C

(S)-N*1*-[7-(2- Cyclopropyl-ethyl)-2- pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine 564 C

S)-N*1*-[7-Bromo-2-(1- oxy-pyridin- 4-yl)-thieno[3,2- d]pyrimidin-4-yl]-3-phenyl-propane-1,2- diamine 565 C

(S)-N*1*-[2-(1-Oxy- pyridin-4-yl)-7- (2H-pyrazol-3-yl)-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 566 B

N*4*-((S)-2-Amino-3- phenyl-propyl)- 2-pyridin-4-yl-thieno[3,2-d]pyrimidine-4,7-diamine 567 C

2-Pyridin-4-yl-N*4*-(R)- pyrrolidin-3-yl-thieno[3,2-d]pyrimidine-4,7-diamine 568 B

(S)-N*1*-[7-(5-Methyl- isoxazol-3-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 569 A

(S)-N*1*-[7-(5-Methyl- 1H-pyrazol-3- yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4- yl]-3-phenyl-propane-1,2- diamine 570 C

(S)-N*1*-[7-(5-Ethyl- isoxazol-3-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 571 A

(S)-N*1*-[7-(5-Ethyl-2H- pyrazol-3-yl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin- 4-yl]-3-phenyl-propane- 1,2-diamine 572 B

(S)-N*1*-(7-Isoxazol-3- yl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-1,2- diamine 573 C

[2-(2-Phenylamino- pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 574 C

Furan-2-carboxylic acid {4-[4-((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-yl}-amide 575 B

1-Phenyl-3-{4-[4-((R)- pyrrolidin-3-ylamino)- thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-yl}-urea 576 D

N-{4-[4-((R)-Pyrrolidin-3- ylamino)- thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-yl}- benzenesulfonamide 577 B

{2-[2-(Pyrazin-2- ylamino)-pyridin-4-yl]- thieno[3,2-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl- amine 578 B

(S)-Tetrahydro-furan-2- carboxylic acid {4-[4- ((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-2-yl]-pyridin- 2-yl}-amide 579 C

[2-(5-Fluoro-2- phenylamino-pyridin-4- yl)-thieno[3,2-d]pyrimidin-4-yl]-(R)- pyrrolidin-3-yl-amine 580 B

{2-[5-Fluoro-2-(pyrazin-2- ylamino)-pyridin-4-yl]-thieno[3,2-d]pyrimidin-4- yl}-(R)-pyrrolidin-3-yl- amine 581 C

1,1-Dimethyl-3-{4-[4- ((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-yl}-urea 582 C

1-tert-Butyl-3-{4-[4-((R)- pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-2- yl]-pyridin-2-yl}-urea 583 C

1-Methyl-3-{4-[4-((R)- pyrrolidin-3-ylamino)- thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-yl}-urea 584 C

Piperidine-1-carboxylic acid {4-[4-((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-2-yl]-pyridin- 2-yl}-amide 585 C

{2-[3-Fluoro-2-(pyrazin-2- ylamino)-pyridin-4-yl]-thieno[3,2-d]pyrimidin-4- yl}-(R)-pyrrolidin-3-yl- amine 586 B

{2-[2-((R)-1-Phenyl- ethylamino)-pyridin-4-yl]-thieno[3,2-d]pyrimidin-4- yl}-(R)-pyrrolidin-3-yl- amine 587 B

{2-[2-((S)-1-Phenyl- ethylamino)-pyridin-4-yl]-thieno[3,2-d]pyrimidin-4- yl}-(R)-pyrrolidin-3-yl- amine 588 B

{2-[2-(6-Methyl- pyridazin-3-ylamino)- pyridin-4-yl]-thieno[3,2-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 589 C

{2-[2-((S)-1-Phenyl- propylamino)-pyridin-4- yl]-thieno[3,2-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 590 C

{2-[2-((R)-1-Phenyl- propylamino)-pyridin-4- yl]-thieno[3,2-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 591 C

(S)-1-{4-[4-((R)- Pyrrolidin-3-ylamino)- thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-ylamino}- propan-2-ol 592 C

(R)-1-{4-[4-((R)- Pyrrolidin-3-ylamino)- thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-ylamino}- propan-2-ol 593 C

(R)-1-Phenyl-2-{4-[4- ((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-ylamino}-ethanol 594 C

[2-(2-Cyclopropylamino- pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 595 B

Thiophene-2-carboxylic acid {4-[4-((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-2-yl]-pyridin- 2-yl}-amide 596 B

3-Methoxy-N-{4-[4-((R)- pyrrolidin-3-ylamino)- thieno[3,2-d]pyrimidin-2-yl]-pyridin-2-yl}- benzamide 597 C

{2-[2- (Cyclopropylmethyl- amino)-pyridin-4-yl]-thieno[3,2-d]pyrimidin-4- yl}-(R)-pyrrolidin-3-yl- amine 598 C

[2-(2-Benzylamino- pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 599 B

Cyclopropanecarboxylic acid {4-[4-((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-2-yl]-pyridin- 2-yl}-amide 600 C

{2-[2-(Pyridin-2- ylamino)-pyridin-4-yl]- thieno[3,2-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl- amine 601 B

{2-[2-(5-Phenyl-pyridin-2- ylamino)-pyridin-4-yl]-thieno[3,2-d]pyrimidin-4- yl}-(R)-pyrrolidin-3-yl- amine 602 B

{2-[2-(5-Morpholin-4-yl- pyridin-2-ylamino)- pyridin-4-yl]-thieno[3,2-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 603 B

(2-{2-[5-(4-Methyl- piperazin-1-yl)- pyridin-2-ylamino]-pyridin-4-yl}-thieno[3,2- d]pyrimidin-4-yl)-(R)- pyrrolidin-3-yl-amine604 B

6-{4-[4-((R)-Pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-ylamino}-nicotinonitrile 605 B

(2-{2-[3-(4-Methyl- piperazin-1-yl)- phenylamino]-pyridin-4-yl}-thieno[3,2- d]pyrimidin-4-yl)-(R)- pyrrolidin-3-yl-amine 606 C

3-{4-[4-((R)-Pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-ylamino}-benzonitrile 607 C

4-{4-[4-((R)-Pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-ylamino}-benzonitrile 608 B

{2-[2-(4-Piperidin-1-yl- phenylamino)-pyridin-4- yl]-thieno[3,2-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 609 B

6-{4-[4-((R)-Pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-ylamino}-nicotinonitrile 610 C

N,N-Dimethyl-4-{4-[4- ((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-ylamino}- benzenesulfonamide 611 C

(R)-Pyrrolidin-3-yl-{2-[2- (4-pyrrolidin-1-ylmethyl-phenylamino)-pyridin-4- yl]-thieno[3,2-]pyrimidin- 4-yl}-amine 612 C

(2-{2-[3-(Propane-2- sulfonyl)-phenylamino]- pyridin-4-yl}-thieno[3,2-d]pyrimidin-4-yl)-(R)- pyrrolidin-3-yl-amine 613 B

(4-Methyl-piperazin-1-yl)- (4-{4-[4-((R)-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-2-yl]-pyridin- 2-ylamino}-phenyl)-methanone 614 B

{2-[2-(4-Imidazol-1- ylmethyl-phenylamino)- pyridin-4-yl]-thieno[3,2-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 615 C

Pyrazine-2-carboxylic acid {4-[4-((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-yl}-amide 616 B

(R)-Pyrrolidin-3-yl-{2-[2- (4-thiophen-2-yl- phenylamino)-pyridin-4-yl]-thieno[3,2- d]pyrimidin-4-yl}-amine 617 B

(R)-Pyrrolidin-3-yl-{2-[2- (4-thiophen-3-yl- phenylamino)-pyridin-4-yl]-thieno[3,2- d]pyrimidin-4-yl}-amine 618 B

4-Fluoro-N-{4-[4-((R)- pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-yl}-benzamide 619 D

[2-(3-Fluoro-2- phenylamino-pyridin- 4-yl)-thieno[3,2-d]pyrimidin-4-yl]- (R)-pyrrolidin-3-yl-amine 620 B

4-(4-Methyl-piperazin-1- yl)-N-{4-[4-((R)- pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-2- yl]-pyridin-2-yl}- benzamide 621 B

4-Morpholin-4-yl-N-{4- [4-((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-yl}-benzamide 622 D

Cyclopropanesulfonic acid {4-[4-((R)-pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-yl}-amide 623 D

[2-(2-Cyclohexylamino- pyridin-4-yl)-thieno[3,2- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 624 D

N-{4-[4-((R)-Pyrrolidin-3- ylamino)-thieno[3,2-d]pyrimidin-2-yl]-pyridin- 2-yl}-methanesulfonamide 625 D

(R)-Pyrrolidin-3-yl-{2-[2- (tetrahydro-pyran-4- ylamino)-pyridin-4-yl]-thieno[3,2-d]pyrimidin-4- yl}-amine 626 C

[2-(2-Isopropylamino- pyridin-4-yl)- thieno[3,2-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl- amine 627 C

Thiophene-2-carboxylic acid {4-[4-((3S,4S)-4- hydroxy-pyrrolidin-3-ylamino)-thieno[3,2- d]pyrimidin-2-yl]-pyridin 2-yl}-amide 628 C

Thiophene-2-carboxylic acid {4-[4-((R)-1-methyl- pyrrolidin-3-ylamino)-thieno[3,2-d]pyrimidin-2- yl]-pyridin-2-yl}-amide 629 C

Thiophene-2-carboxylic acid {4-[4-((3S,4S)-1- carbamoylmethyl-4-hydroxy-pyrrolidin-3- ylamino)-thieno[3,2- d]pyrimidin-2-yl]-pyridin-2-yl}-amide 630 D

Thiophene-2-carboxylic acid (4-{4-[(S)-2-amino-3- (4-trifluoromethyl-phenyl)-propylamino]- thieno[3,2-d]pyrimidin-2- yl}-pyridin-2-yl)-amide631 D

2-{(R)-3-[2-(2- Phenylamino-pyridin- 4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]- pyrrolidin-1-yl}-acetamide 632 C

633 D

[2-(5-Methyl-1H-pyrazol- 4-yl)-thieno[3,2- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 634 C

(S)-N*1*-[2-(5-Methyl- 1H-pyrazol-4- yl)-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2- diamine

Preferably, a compound of the present invention (i.e., a compound offormula (I) or a salt thereof) has an IC₅₀ in an IMAP assay against fulllength PKCι at 150 μM ATP of <40 μM. In one embodiment, a compound ofthe present invention has an IC₅₀ in an IMAP assay against full lengthPKCι at 15 μM ATP of 40 μM-10 μM. More preferably, a compound of thepresent invention has an IC₅₀ in an IMAP assay against full length PKCιat 15 μM ATP of 10 μM-1 μM. In one embodiment, a compound of the presentinvention has an IC₅₀ in an IMAP assay against full length PKCι at 15 μMATP of 1 μM-0.1 μM. More preferably, a compound of the present inventionhas an IC₅₀ in an IMAP assay against full length PKCι at 15 μM ATP of<0. μM.

Preferably, a compound of the present invention (i.e., a compound offormula (I) or a salt thereof) has an IC₅₀ in an IMAP assay againstkinase domain PKCι at 25 μM ATP of <4 μM. In one embodiment, a compoundof the present invention has an IC₅₀ in an IMAP assay against kinasedomain PKCι at 25 μM ATP of 40 μM-10 μM. More preferably, a compound ofthe present invention has an IC₅₀ in an IMAP assay against kinase domainPKCι at 2 μM ATP of 10 μM-1 μM. In one embodiment, a compound of thepresent invention has an IC₅₀ in an IMAP assay against kinase domainPKCι at 2 μM ATP of 1 μM-0.1 μM. More preferably, a compound of thepresent invention has an IC₅₀ in an IMAP assay against kinase domainPKCι at 2 μM ATP of <0. μM.

As those skilled in the art will appreciate, numerous modifications andvariations of the present invention are possible in light of the aboveteachings. It is therefore understood that within the scope of theappended claims, the invention may be practiced otherwise than asspecifically described herein, and the scope of the invention isintended to encompass all such variations.

Each publication referenced herein is incorporated by reference in itsentirety for all purposes.

Additional Preferred Embodiments of the present invention include:

1. A compound of formula (I)

or a salt form thereof,wherein

-   -   A is NR¹¹, O, or S;    -   M-Q-X is a group of formula

-   -   G is a group of formula

-   -   R¹, R², R¹¹, and R¹⁷ are independently chosen from H, C₁₋₆alkyl        optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by        1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹, and —OR²⁰    -   R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R⁸        are independently chosen from H, C₁₋₆alkyl optionally        substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by        1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,        C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl        optionally substituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally        substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyl optionally        substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyl        optionally substituted by 1-28 R¹⁹, 4-21 membered        heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15        membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21        membered heteroarylalkyl optionally substituted by 1-27 R¹⁹,        halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³,        —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³,        —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰,        —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,        —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,        —NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(═NR²⁵)NR²²R²³,        —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰,        —NR²⁴C(═S)NR²²R²³, —R²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,        —NR²⁴P(═O)R²⁸R²⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³),        —NR²⁴P(═O)(OR²⁰)(OR²⁰), —NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN,        —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³,        —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,        —OP(═O)R²⁸R²⁸, —OP(═O)(NR²²R²³)(NR²²R²³), —OP(═O)(OR²⁰)(OR²⁰),        —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,        —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,        —SP(═O)R²⁸R²⁸R²⁸, —SP(═O)(NR²²R²³)(NR²²R²³),        —SP(═O)(OR²⁰)(OR²⁰), —SP(═O)(SR²⁰)(SR²⁰), —P(═O)R²⁸R²⁸,        —P(═O)(NR²²R²³)(2R²²R²³), —P(═O)(OR²⁰)(OR²⁰), and        —P(═O)(SR²⁰)(SR²⁰);    -   any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹,        R⁶ and R¹¹, and R¹⁶ and R¹⁷ can, together with the atoms linking        them, form a 3-15 membered heterocycloalkyl optionally        substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionally        substituted by 1-15 R¹⁹;    -   any of R³ and R⁶, R⁷ and R⁸, R⁹ and R¹⁰, R¹² and R¹³, and R¹⁴        and R¹⁵ can, together with the atoms linking them, form a        C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl        optionally substituted by 1-21 R¹⁹, 3-15 membered        heterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15        membered heteroaryl optionally substituted by 1-15 R¹⁹;    -   R³ and R⁵ or R⁴ and R⁶ can together form a double bond;    -   any of R³ and R⁴, and R⁵ and R⁶ can together form ═O, ═NR²⁰,        ═NOR²⁰, or ═S;    -   R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R³⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R³⁹, C₂₋₆alkynyl optionally substituted by        1-9 R³⁹, C₆₋₁₁aryl optionally substituted by 1-11 R³⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R³⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R³⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R³⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R³⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R³⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R³⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³,        —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰, —C(═NR³⁵)NR³²R³³, —C(═NOH)NR³²R³³,        —C(═NOR³⁶)R³⁰, —C(═NNR³²R³³)R³⁰, —C(═NNR³⁴C(═O)R³¹)R³⁰,        —C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂, —NR³²R³³,        —NR³⁴NR³²R³³, —N═NR³⁴═NR³⁰, ═NOR³⁰, —NR³⁴R³⁶, —NR³⁴C(═O)R³⁰,        —NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,        —NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰,        —NR³⁴C(═O)NR³⁴C(═O)OR³⁰, —NR³⁴C(═NR³⁵)NR³²R³³,        —NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴C(═S)R³⁰, —NR³⁴C(═S)OR³⁰,        —NR³⁴C(═S)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,        —NR³⁴P(═O)R³⁸R³⁸, —NR³⁴P(═O)(NR³²R³³)(NR³²R³³,        —NR³⁴P(═O)(OR³⁰)(OR³⁰), —NR³⁴P(═O)(SR³⁰)(SR³⁰), —OR³⁰, ═O, —OCN,        —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,        —OS(═O)R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂NR³²R³³,        —OP(═O)R³⁸R³⁸, —OP(═O)(NR³²R³³)(NR³²R³³), —OP(═O)(OR³⁰)(OR³⁰),        —OP(═O)(SR³⁰)(SR³⁰), —Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰,        —S(═O)₂₀R³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,        —SP(═O)R³⁸R³⁸, —SP(═O)(NR³²R³³)(NR³²R³³), —SP(═O)(OR³⁰)(OR³⁰),        —SP(═O)(SR³⁰)(SR³⁰), —P(═O)R³⁸R³⁸, —P(═O)(NR³²R³³)(NR³²R³³),        —P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰);    -   R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at        each occurrence is independently chosen from H, C₁₋₆alkyl        optionally substituted by 1-13 R⁴⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R⁴⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁴⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁴⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁴⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁴⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁴⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁴⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁴⁹;    -   R²⁸ and R³⁸ at each occurrence is independently chosen from        C₁₋₆alkyl optionally substituted by 1-13 R⁴⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁴⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁴⁹, C₆₋₁₁-aryl optionally substituted by        1-11 R⁴⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁴⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁴⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁴⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁴⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁴⁹;    -   R²², R²³, R³² and R³³ at each occurrence is independently chosen        from H, C₁₋₆alkyl optionally substituted by 1-13 R⁵⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R⁵⁹, C₃₋₁₁-cycloalkyl optionally substituted by 1-21        R⁵⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁵⁹,        3-15 membered heterocycloalkyl optionally substituted by 1-28        R⁵⁹, 4-21 membered heterocycloalkylalkyl optionally substituted        by 1-40 R⁵⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁵⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁵⁹;        -   or any R²² and R²³ and/or R³² and R³³ may form, together            with the nitrogen atom to which they are attached, a 3-15            membered heterocycloalkyl optionally substituted by 1-28 R⁶⁹            or a 5-15 membered heteroaryl optionally substituted by 1-15            R⁶⁹    -   R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen        from C₁₋₆ alkyl optionally substituted by 1-13 R⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁷⁹,        C₃₋₁₁-cycloalkyl optionally substituted by 1-21 R⁷⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁷⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁷⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³,        —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰, —C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³,        —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰, —C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰,        —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³,        —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴⁰R⁷⁶, —NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)C(═O)R⁷⁰, —R⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═O)OR,        —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰, —NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³,        —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —R⁷⁴C(═S)R⁷⁰, —NR⁷⁴C(═S)OR⁷⁰,        —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,        —NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —NR⁷⁴P(═O)(OR⁷⁰)(OR⁷⁰), —NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, ═O, —OCN,        —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³,        —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —OP(═O)(OR⁷⁰)(OR⁷⁰),        —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S, —S(═O)_(n)R⁷⁰,        —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),        —SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰);    -   R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁸⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R⁸⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R⁸⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R⁸⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R⁸⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32        R⁸⁹, 3-15 membered heterocycloalkyl optionally substituted by        1-28 R⁸⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R⁸⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R⁸⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R⁸⁹;    -   R⁷² and R⁷³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R⁹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁹⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁹⁹,        C₄-17cycloalkylalkyl optionally substituted by 1-32 R⁹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁹⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁹⁹; or any R⁷² and R⁷³ may form, together        with the nitrogen atom to which they are attached, a 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁰⁹ or        a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁰⁹;    -   R⁷⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R⁸⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R⁸⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁸⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁸⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁸⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁸⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁸⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁸⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁸⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁸⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁸⁹;    -   R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently        chosen from C₁₋₆ alkyl optionally substituted by 1-13 halogen,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl,        C₃₋₁₁cycloalkyl, C₄₋₁₇cycloalkylalkyl, 3-15 membered        heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15        membered heteroaryl, 6-21 membered heteroarylalkyl, halogen,        —CN, —C(═O)R¹¹⁰, —C(═O)OR¹¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —C(═O)C(═O)R¹¹⁰,        —C(═NR¹¹⁰)R¹¹⁰, —C(═NR¹¹⁰NR¹¹⁰R¹¹⁰, —C(═NOH)NR¹¹⁰R¹¹⁰,        —C(═NOR¹¹⁰)R¹¹⁰, —C(═NNR¹¹⁰R¹¹⁰)R¹⁰, —C(═NNR¹¹⁰C(═O)R¹¹⁰)R¹¹⁰,        —C(═NNR¹¹⁰C(═O)OR¹¹⁰)R¹¹⁰, —C(═S)NR¹¹⁰R¹¹⁰, —NC, —NO₂,        —NR¹¹⁰R¹¹⁰, —NR¹¹⁰NR¹¹⁰R¹¹⁰, —N═NR¹¹⁰, ═NR¹¹⁰, ═NOR¹¹⁰,        —NR¹¹⁰OR¹¹⁰, —NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)C(═O)R¹¹⁰,        —NR¹¹⁰C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)C(═O)OR¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰,        —NR¹¹⁰C(═O)NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰C(═O)OR¹¹⁰,        —NR¹¹⁰C(═NR¹¹⁰)NR¹¹⁰R¹¹⁰, —NR¹¹⁰C(═O)C(═O)NR¹¹⁰R¹¹⁰,        —NR¹¹⁰C(═S)R¹¹⁰, —NR¹¹⁰C(═S)OR¹¹⁰, —NR¹¹⁰C(═S)NR¹¹⁰R¹¹⁰,        —NR¹¹⁰S(═O)₂R¹¹⁰, —NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰, —NR¹¹⁰P(═O)R¹¹¹R¹¹¹,        —NR¹¹⁰P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —NR¹¹⁰P(═O)(OR¹¹⁰)(OR¹¹⁰),        —NR¹¹⁰P(═O)(SR¹¹⁰)(SR¹¹⁰), —OR¹¹⁰, =, —OCN, —OC(═O)R¹¹⁰,        —OC(═O)NR¹¹⁰R¹¹⁰, —OC(═O)OR¹¹⁰, —OC(═NR¹¹⁰) NR¹¹⁰R¹¹⁰,        —OS(═O)R¹¹⁰, —OS(═O)₂R¹¹⁰, —OS(═O)₂OR¹¹⁰, —OS(═O)₂NR¹¹⁰R¹¹⁰,        —OP(═O)R¹¹¹R¹¹¹, —OP(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰),        —OP(═O)(OR¹¹⁰)(OR¹¹⁰), —OP(═O)(SR¹¹⁰)(SR¹¹⁰), —Si(R¹¹⁰)₃, —SCN,        ═S, —S(═O)_(n)R¹¹⁰, —S(═O)₂OR¹¹⁰, —SO₃R¹¹⁰, —S(═O)₂NR¹¹⁰R¹¹⁰,        —S(═O)NR¹¹⁰R¹¹⁰, —SP(═O)R¹¹¹R¹¹¹, —SP(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰),        —SP(═O)(OR¹¹⁰)(OR¹¹⁰), —SP(═O)(SR¹¹⁰)(SR¹¹⁰), —P(═O)R¹¹¹R¹¹¹,        —P(═O)(NR¹¹⁰R¹¹⁰)(NR¹¹⁰R¹¹⁰), —P(═O)(OR¹¹⁰)(OR¹¹⁰), and        —P(═O)(SR¹¹⁰)(SR¹¹⁰);    -   R¹¹⁰ at each occurrence is independently chosen from H,        C₁₋₆alkyl and C₁₋₆-haloalkyl;    -   R¹¹¹ at each occurrence is independently chosen from C₁₋₆alkyl        and C₁₋₆-haloalkyl; and    -   n at each occurrence is independently chosen from 0, 1, and 2.        2. A compound as defined in Preferred Embodiment 1, wherein A is        NR¹¹.        3. A compound as defined in Preferred Embodiments 1 or 2,        wherein G is a group of formula

4. A compound as defined in Preferred Embodiment 3, wherein G is a groupof formula

and the compound of formula (I) is a compound of formula (Ic)

5. A compound as defined in any of Preferred Embodiments 1-4, whereinR¹, R², and R¹¹ are independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen fromH, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, R³ and R⁶ can, together with the atoms linking them, forma C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-3 R¹⁹; alternatively R³ and R⁵ or R⁴ and R⁶can together form a double bond; and alternatively any of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, togetherwith the atoms linking them, form a 5-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-3 R¹⁹.6. A compound as defined in any of Preferred Embodiments 1-4, whereinR¹, R², and R¹¹ are independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹; R³, R⁴, R⁵, and R⁶ are independently chosen fromH, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively any of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, togetherwith the atoms linking them, form a 5-15 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹.7. A compound as defined in any of Preferred Embodiments 1-4, whereinR¹, R⁴, R⁵, R⁶, and R¹¹ are independently chosen from H and C₁₋₆alkyloptionally substituted by 1-13 R¹⁹; R² is chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹;alternatively, R³ and R⁶ can, together with the atoms linking them, forma C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹; alternatively R³and R⁴ can together form ═O; and alternatively any of R and R², R andR³, R and R⁵, R and R¹¹, R⁴ and R¹¹, and R⁶ and R¹¹ can, together withthe atoms linking them, form a 3-15 membered heterocycloalkyl optionallysubstituted by 1-22 R¹⁹.8. A compound as defined in any of Preferred Embodiments 1-4, whereinR¹, R⁴, R⁵, R⁶, and R¹¹ are independently chosen from H and C₁₋₆alkyloptionally substituted by 1-3 R¹⁹; R² is chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R¹⁹, and 6-10 membered heteroarylalkyl optionally substituted by1-3 R¹⁹; R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, and 6-11 membered heteroarylalkyloptionally substituted by 1-7 R¹⁹; and alternatively any of R¹ and R²,R¹ and R³, R¹ and R⁵, R¹ and R¹¹, and R⁴ and R¹¹ can, together with theatoms linking them, form a 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.9. A compound as defined in any of Preferred Embodiments 1-8, whereinR⁷, R⁸, R⁹, and R¹⁰ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹,C₄₋₈cycloalkylalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 4-8 memberedheterocycloalkylalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰,and —S(═O)₂NR²²R²³; alternatively, either or both of R⁷ and R⁸, and/orR⁹ and R¹⁰, can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3R¹⁹ or a 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.10. A compound as defined in any of Preferred Embodiments 1-8, whereinR⁷, R⁸, R⁹, and R¹⁰ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₃₋₇cycloalkyl optionallysubstituted by 1-3 R¹⁹, or a 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹.11. A compound as defined in any of Preferred Embodiments 1-8, whereinR⁷, R⁸, R⁹, and R¹⁰ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.12. A compound as defined in any of Preferred Embodiments 1-8, whereinR⁷ and R¹⁰ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; R and R⁹are independently chosen from C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆11aryl optionally substituted by1-3 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹,C₃11cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, C₃11cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹.13. A compound as defined in any of Preferred Embodiments 1-8, whereinR⁷, R⁸, R⁹, and R¹⁰ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.14. A compound as defined in any of Preferred Embodiments 1-8, whereinR⁷, R⁸, R⁹, and R¹⁰ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, phenyloptionally substituted by 1-3 R¹⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R¹⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3R¹⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹ halogen,—CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰;alternatively, either or both of R⁷ and R⁸, and/or R⁹ and R¹⁰, can,together with the atoms linking them, form a phenyl optionallysubstituted by 1-3 R¹⁹, C₃₋₆ cycloalkyl optionally substituted by 1-3R¹⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.15. A compound as defined in any of Preferred Embodiments 1-14, whereinR¹², R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —R²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰,—S(═O)₂₀R²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R²⁸R²⁸,—P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); alternatively, eitheror both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atomslinking them, form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹.16. A compound as defined in any of Preferred Embodiments 1-14, whereinR¹², R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; alternatively, either or bothof R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linkingthem, form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.17. A compound as defined in any of Preferred Embodiments 1-14, whereinR¹², R¹³, and R¹⁴ are H; R¹⁵ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.18. A compound as defined in any of Preferred Embodiments 1-14, whereinR¹², R¹³, R¹⁴, and R¹⁵ are independently chosen from H, halogen,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.19. A compound as defined in any of Preferred Embodiments 1-14, whereinR¹², R¹³, and R¹⁵ are H; R¹⁴ is chosen from H, halogen, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —OR²⁰, and —S(═O)₂NR²²R²³.20. A compound as defined in any of Preferred Embodiments 1-3 or 5-19,wherein R¹⁷ is chosen from H and C₁₋₆alkyl; R¹⁶ and R¹⁸ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC,—NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, and —S(═O)NR²²R²³;alternatively, R¹⁶ and R¹⁷ can, together with the atoms linking them,form a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹or a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.21. A compound as defined in any of Preferred Embodiments 1-3 or 5-19,wherein R¹⁷ is chosen from H and C₁₋₆alkyl; R¹⁶ and R¹⁸ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-3 R¹⁹ halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;alternatively, R¹⁶ and R¹⁷ can, together with the atoms linking them,form a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹or a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.22. A compound as defined in any of Preferred Embodiments 1-3 or 5-19,wherein R¹⁷ is H; and R¹⁶ and R¹⁸ are independently chosen from H andC₁₋₆alkyl optionally substituted by 1-3 R¹⁹.23. A compound as defined in any of Preferred Embodiments 1-3 or 5-19,wherein R¹⁷ is H; and R¹⁶ and R¹⁸ are independently chosen from H andC₁₋₆alkyl.24. A compound as defined in any of Preferred Embodiments 1-23, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹,C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R³⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)NR³²R³³, —R³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.25. A compound as defined in any of Preferred Embodiments 1-23, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by 1-3 R³⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R³⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R³⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)NR³²R³³,—NR³²R³³, —NR³⁴C(═O)R³⁰, —NR³⁴S(═O)₂R³¹, —OR³⁰, ═O, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.26. A compound as defined in any of Preferred Embodiments 1-23, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3R³⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R³⁹,5-6 membered heteroaryl optionally substituted by 1-3 R³⁹, halogen,—C(═O)OR³⁰, —NR³²R³³, and —OR³⁰.27. A compound as defined in any of Preferred Embodiments 1-23, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl, phenyloptionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl, halogen, —C(═O)OR³⁰, —NR³²R³³ and —OR³⁰.28. A compound as defined in any of Preferred Embodiments 1-27, whereinR²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R⁴⁹, C₂₋₆ alkenyl optionally substituted by 1-6 R⁴⁹,C₂₋₆alkynyl optionally substituted by 1-6 R⁴⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R⁴⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6R⁴⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁴⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R⁴⁹, and 5-10 memberedheteroaryl optionally substituted by 1-6 R⁴⁹.29. A compound as defined in any of Preferred Embodiments 1-27, whereinR²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, benzyloptionally substituted by 1-3 R⁴⁹, C₃₋₆ cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 3-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹.30. A compound as defined in any of Preferred Embodiments 1-27, whereinR²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹ 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.31. A compound as defined in any of Preferred Embodiments 1-27, whereinR²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.32. A compound as defined in any of Preferred Embodiments 1-27, whereinR²⁰ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.33. A compound as defined in any of Preferred Embodiments 1-32, whereinR²⁸ and R³⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, C₂₋₆alkenyl optionally substituted by1-3 R⁴⁹, C₂₋₆alkynyl optionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryloptionally substituted by 1-3 R⁴⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R⁴⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-10memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.34. A compound as defined in any of Preferred Embodiments 1-33, whereinR²², R²³, R³² and R³³ at each occurrence is independently chosen from H,C₁₋₆alkyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl, 3-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl.35. A compound as defined in any of Preferred Embodiments 1-33, whereinR²² at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁵⁹, C₂₋₆alkenyl optionally substituted by1-3 R⁵⁹, C₂₋₆alkynyl optionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryloptionally substituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆alkyl;alternatively, any R²² and R²³ and/or R³² and R³³ may form, togetherwith the nitrogen atom to which they are attached, a 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁶⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R⁶⁹.36. A compound as defined in any of Preferred Embodiments 1-33, whereinR²² at each occurrence is independently chosen from H, phenyl optionallysubstituted by 1 R⁵⁹, and 6 membered heteroaryl optionally substitutedby 1 R⁵⁹; R²³, R³² and R³³ at each occurrence is independently chosenfrom H and C₁₋₆alkyl.37. A compound as defined in any of Preferred Embodiments 1-36, whereinR³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R⁷⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R⁷⁹, C₂₋₆alkynyl optionally substituted by 1-3 R⁷⁹,C₆₋₁₀aryl optionally substituted by 1-3 R⁷⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R⁷⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R⁷⁹,5-10 membered heteroaryl optionally substituted by 1-3 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, ═O,—S(═O)_(n)R⁷⁰ and —S(═O)₂NR⁷²R⁷³.38. A compound as defined in any of Preferred Embodiments 1-37, whereinR³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-9 memberedheteroaryl, —CN, and —C(═O)R⁷⁰.39. A compound as defined in any of Preferred Embodiments 1-38, whereinR⁷⁰, R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-3 R⁸⁹, C₆₋₁₀aryloptionally substituted by 1-3 R⁸⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R⁸⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁸⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-10membered heteroaryl optionally substituted by 1-3 R⁸⁹.40. A compound as defined in any of Preferred Embodiments 1-38, whereinR⁷⁰, R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independentlychosen from H, C₁₋₆alkyl, and 5-6 membered heterocycloalkyl.41. A compound as defined in any of Preferred Embodiments 1-40, whereinR⁷² and R⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹, C₂₋₆alkenyl optionally substituted by1-3 R⁹⁹, C₂₋₆ alkynyl optionally substituted by 1-3 R⁹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R⁹⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R⁹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁹⁹, 3-10memberedheterocycloalkyl optionally substituted by 1-3 R⁹⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁹⁹; alternatively, any R⁷² andR⁷³ may form, together with the nitrogen atom to which they areattached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3R¹⁰⁹ or a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁰⁹.42. A compound as defined in any of Preferred Embodiments 1-40, whereinR⁷² and R⁷³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; alternatively, any R⁷²and R⁷³ may form, together with the nitrogen atom to which they areattached, a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.43. A compound as defined in any of Preferred Embodiments 1-42, whereinR⁷⁸ at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁸⁹,C₂₋₆alkynyl optionally substituted by 1-3 R⁸⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁸⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁸⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁸⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁸⁹.44. A compound as defined in any of Preferred Embodiments 1-42, whereinR⁷⁸ at each occurrence is independently chosen from C₁₋₆alkyl, phenyl,benzyl, C₃₋₆ cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.45. A compound as defined in any of Preferred Embodiments 1-44, whereinR⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 halogen, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀aryl, C₇₋₁₁ arylalkyl, C₃₋₁₀cycloalkyl, 3-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹⁰, —C(═O)NR¹¹⁰R¹¹⁰, —NO₂, —NR¹¹⁰R¹¹⁰, —NR¹¹⁰OR¹¹⁰,—NR¹¹⁰C(═O)R¹¹⁰, —NR¹¹⁰C(═O)NR¹¹⁰R¹¹⁰, —NR¹¹⁰S(═O)₂R¹¹⁰,—NR¹¹⁰S(═O)₂NR¹¹⁰R¹¹⁰, —OR¹¹⁰, ═O, —OCN, —OC(═O)R¹¹⁰, —S(═O)R¹¹⁰,—S(═O)₂NR¹¹⁰R¹¹⁰, and —S(═O)NR¹¹⁰R¹¹⁰.46. A compound as defined in any of Preferred Embodiments 1-45, whereinR¹¹⁰ at each occurrence is independently chosen from H, C₁₋₆alkyl andC₁₋₆-haloalkyl.47. A compound as defined in any of Preferred Embodiments 1-46, whereinR¹¹ at each occurrence is independently chosen from C₁₋₆alkyl andC₁₋₆-haloalkyl.

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, of formula I:

wherein, R¹, R², and R¹¹ are independently chosen from H and C₁₋₆alkyloptionally substituted by 1-13 R¹⁹; R³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R¹⁹, C₇₋₁₁ arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; R⁴, R⁵, and R⁶ are H; R⁷ is selected from H and C₁₋₆alkyloptionally substituted by 1-3 R¹⁹; R⁸ is selected from C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹; R¹², R¹³, R¹⁴, and R¹⁵ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, —R²⁴C(═O)NR²²R²³, —OR²⁰, and—S(═O)₂NR²²R²³; R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,halogen, —C(═O)OR³⁰ and —OR³⁰; and R²⁰, R²², R²³, R²⁴, and R³⁰ at eachoccurrence are independently chosen from H and C₁₋₆alkyl.
 2. Thecompound, or pharmaceutically acceptable salt thereof, according toclaim 1 wherein R¹ and R² are H.
 3. The compound, or pharmaceuticallyacceptable salt thereof, according to claim 1 wherein R¹¹ is H.
 4. Thecompound, or pharmaceutically acceptable salt thereof, according toclaim 1 wherein R¹, R² and R¹¹ are H.
 5. The compound, orpharmaceutically acceptable salt thereof, according to claim 1 whereinR³ is selected from C₁₋₆alkyl optionally substituted by 1-13 R¹⁹ andC₇₋₁₁arylalkyl optionally substituted by 1-9 R¹⁹.
 6. The compound, orpharmaceutically acceptable salt thereof, according to claim 1 whereinR⁷ is H.
 7. The compound, or pharmaceutically acceptable salt thereof,according to claim 1 wherein R¹⁹ is selected from C₁₋₆alkyl, phenyl,C₃₋₆cycloalkyl, halogen and —OR³⁰.
 8. The compound, or pharmaceuticallyacceptable salt thereof, according to claim 1 wherein R¹², R¹³, R¹⁴, andR¹⁵ are independently chosen from H and halogen.
 9. The compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of: Structure Name

(S)-N*1*-[7-(3-Methoxy-prop- 1-ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine

4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro-pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-but-3-yn-1-ol

4-[4-((S)-2-Amino-3-phenyl- propylamino)-6-methyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-7-yl]-2-methyl-but- 3-yn-2-ol

4-[4-((S)-2-Amino-3-phenyl- propylamino)-6-tert-butyl-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-7-yl]-2-methyl-but- 3-yn-2-ol

3-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro-pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-prop-2-yn-1- ol

1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro-pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-ylethynyl]- cyclobutanol

(S)-4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro-pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-but-3-yn-2-ol

4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro-pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-2-methyl-but- 3-yn-2-ol

4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-2- methyl-but-3-yn-2-ol

4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- but-3-yn-2-ol

3-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- prop-2-yn-1-ol

S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- pent-1-yn-3-ol

(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-4- methyl-hept-1-yn-3-ol

(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-3- methyl-pent-1-yn-3-ol

(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- 3,4-dimethyl-pent-1-yn-3-ol

1-[4-(2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-3- ethyl-pent-1-yn-3-ol

(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- hex-1-yn-3-ol

1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7- ylethynyl]-cyclopentanol

4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- but-3-yn-1-ol

1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7- ylethynyl]-cyclopropanol

(S)-4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- but-3-yn-2-ol

(R)-4-[4-((S)-2-Amino-3- phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7- yl]-but-3-yn-2-ol

5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- pent-4-yn-1-ol

5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- pent-4-yn-2-ol

5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-2- methyl-pent-4-yn-2-ol

1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7- ylethynyl]-cyclobutanol

(S)-5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]- pent-4-yn-2-ol

(S)-N*1*-[7-((R)-3-Fluoro-but- 1-ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine

(S)-N*1*-[7-(3-Fluoro-prop-1- ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl- propane-1,2-diamine

(S)-N*1*-[7-(4-Fluoro-but-1- ynyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidine.


10. A pharmaceutical composition comprising a compound of Formula I, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, wherein Formula I is:

wherein, R¹, R², and R¹¹ are independently chosen from H and C₁₋₆alkyloptionally substituted by 1-13 R¹⁹; R³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-9 R¹⁹, C₆₋₇cycloalkylalkyl optionally substituted by1-6 R¹⁹, and 6-11 membered heteroarylalkyl optionally substituted by 1-7R¹⁹; R⁴, R⁵, and R⁶ are H; R⁷ is selected from H and C₁₋₆alkyloptionally substituted by 1-3 R¹⁹; R⁸ is selected from C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹; R¹², R¹³, R¹⁴, and R¹⁵ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —OR²⁰, and—S(═O)₂NR²²R²³; R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,halogen, —C(═O)OR³⁰ and —OR³⁰; and R²⁰, R²², R²³, R²⁴, and R³⁰ at eachoccurrence are independently chosen from H and C₁₋₆alkyl.